Membrane Interaction of Bound Ligands Contributes to the Negative Binding Cooperativity of the EGF Receptor
Events
Loading … Spinner

Mendeley | Further Information

{"title"=>"Membrane Interaction of Bound Ligands Contributes to the Negative Binding Cooperativity of the EGF Receptor", "type"=>"journal", "authors"=>[{"first_name"=>"Anton", "last_name"=>"Arkhipov", "scopus_author_id"=>"7005731529"}, {"first_name"=>"Yibing", "last_name"=>"Shan", "scopus_author_id"=>"18635435600"}, {"first_name"=>"Eric T.", "last_name"=>"Kim", "scopus_author_id"=>"7404507345"}, {"first_name"=>"David E.", "last_name"=>"Shaw", "scopus_author_id"=>"7403342673"}], "year"=>2014, "source"=>"PLoS Computational Biology", "identifiers"=>{"scopus"=>"2-s2.0-84905460438", "sgr"=>"84905460438", "issn"=>"15537358", "doi"=>"10.1371/journal.pcbi.1003742", "pmid"=>"25058506", "pui"=>"373701193"}, "id"=>"619d66e8-7f12-3058-86f0-a6c57cc7a569", "abstract"=>"The epidermal growth factor receptor (EGFR) plays a key role in regulating cell proliferation, migration, and differentiation, and aberrant EGFR signaling is implicated in a variety of cancers. EGFR signaling is triggered by extracellular ligand binding, which promotes EGFR dimerization and activation. Ligand-binding measurements are consistent with a negatively cooperative model in which the ligand-binding affinity at either binding site in an EGFR dimer is weaker when the other site is occupied by a ligand. This cooperativity is widely believed to be central to the effects of ligand concentration on EGFR-mediated intracellular signaling. Although the extracellular portion of the human EGFR dimer has been resolved crystallographically, the crystal structures do not reveal the structural origin of this negative cooperativity, which has remained unclear. Here we report the results of molecular dynamics simulations suggesting that asymmetrical interactions of the two binding sites with the membrane may be responsible (perhaps along with other factors) for this negative cooperativity. In particular, in our simulations the extracellular domains of an EGFR dimer spontaneously lay down on the membrane in an orientation in which favorable membrane contacts were made with one of the bound ligands, but could not be made with the other. Similar interactions were observed when EGFR was glycosylated, as it is in vivo.", "link"=>"http://www.mendeley.com/research/membrane-interaction-bound-ligands-contributes-negative-binding-cooperativity-egf-receptor", "reader_count"=>49, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Student > Doctoral Student"=>3, "Researcher"=>15, "Student > Ph. D. Student"=>19, "Student > Postgraduate"=>2, "Student > Master"=>3, "Student > Bachelor"=>4, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>1, "Student > Doctoral Student"=>3, "Researcher"=>15, "Student > Ph. D. Student"=>19, "Student > Postgraduate"=>2, "Student > Master"=>3, "Student > Bachelor"=>4, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>25, "Medicine and Dentistry"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Physics and Astronomy"=>6, "Chemistry"=>9}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Chemistry"=>{"Chemistry"=>9}, "Physics and Astronomy"=>{"Physics and Astronomy"=>6}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>25}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"Canada"=>1, "United States"=>1, "United Kingdom"=>3, "Mexico"=>1, "France"=>1, "Germany"=>2, "India"=>1}, "group_count"=>1}

Scopus | Further Information

{"@_fa"=>"true", "link"=>[{"@_fa"=>"true", "@ref"=>"self", "@href"=>"https://api.elsevier.com/content/abstract/scopus_id/84905460438"}, {"@_fa"=>"true", "@ref"=>"author-affiliation", "@href"=>"https://api.elsevier.com/content/abstract/scopus_id/84905460438?field=author,affiliation"}, {"@_fa"=>"true", "@ref"=>"scopus", "@href"=>"https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84905460438&origin=inward"}, {"@_fa"=>"true", "@ref"=>"scopus-citedby", "@href"=>"https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=84905460438&origin=inward"}], "prism:url"=>"https://api.elsevier.com/content/abstract/scopus_id/84905460438", "dc:identifier"=>"SCOPUS_ID:84905460438", "eid"=>"2-s2.0-84905460438", "dc:title"=>"Membrane Interaction of Bound Ligands Contributes to the Negative Binding Cooperativity of the EGF Receptor", "dc:creator"=>"Arkhipov A.", "prism:publicationName"=>"PLoS Computational Biology", "prism:issn"=>"1553734X", "prism:eIssn"=>"15537358", "prism:volume"=>"10", "prism:issueIdentifier"=>"7", "prism:pageRange"=>nil, "prism:coverDate"=>"2014-01-01", "prism:coverDisplayDate"=>"July 2014", "prism:doi"=>"10.1371/journal.pcbi.1003742", "citedby-count"=>"23", "affiliation"=>[{"@_fa"=>"true", "affilname"=>"D.E. Shaw Research, LLC", "affiliation-city"=>"New York", "affiliation-country"=>"United States"}], "pubmed-id"=>"25058506", "prism:aggregationType"=>"Journal", "subtype"=>"ar", "subtypeDescription"=>"Article", "article-number"=>"e1003742", "source-id"=>"4000151810", "openaccess"=>"1", "openaccessFlag"=>true}

Facebook

  • {"url"=>"http%3A%2F%2Fjournals.plos.org%2Fploscompbiol%2Farticle%3Fid%3D10.1371%252Fjournal.pcbi.1003742", "share_count"=>0, "like_count"=>0, "comment_count"=>0, "click_count"=>0, "total_count"=>0}

Counter

  • {"month"=>"7", "year"=>"2014", "pdf_views"=>"61", "xml_views"=>"3", "html_views"=>"537"}
  • {"month"=>"8", "year"=>"2014", "pdf_views"=>"107", "xml_views"=>"8", "html_views"=>"709"}
  • {"month"=>"9", "year"=>"2014", "pdf_views"=>"49", "xml_views"=>"0", "html_views"=>"163"}
  • {"month"=>"10", "year"=>"2014", "pdf_views"=>"41", "xml_views"=>"0", "html_views"=>"185"}
  • {"month"=>"11", "year"=>"2014", "pdf_views"=>"45", "xml_views"=>"3", "html_views"=>"213"}
  • {"month"=>"12", "year"=>"2014", "pdf_views"=>"34", "xml_views"=>"1", "html_views"=>"127"}
  • {"month"=>"1", "year"=>"2015", "pdf_views"=>"20", "xml_views"=>"0", "html_views"=>"118"}
  • {"month"=>"2", "year"=>"2015", "pdf_views"=>"25", "xml_views"=>"0", "html_views"=>"155"}
  • {"month"=>"3", "year"=>"2015", "pdf_views"=>"33", "xml_views"=>"0", "html_views"=>"123"}
  • {"month"=>"4", "year"=>"2015", "pdf_views"=>"13", "xml_views"=>"1", "html_views"=>"59"}
  • {"month"=>"5", "year"=>"2015", "pdf_views"=>"17", "xml_views"=>"0", "html_views"=>"73"}
  • {"month"=>"6", "year"=>"2015", "pdf_views"=>"29", "xml_views"=>"0", "html_views"=>"65"}
  • {"month"=>"7", "year"=>"2015", "pdf_views"=>"17", "xml_views"=>"0", "html_views"=>"63"}
  • {"month"=>"8", "year"=>"2015", "pdf_views"=>"15", "xml_views"=>"0", "html_views"=>"64"}
  • {"month"=>"9", "year"=>"2015", "pdf_views"=>"12", "xml_views"=>"0", "html_views"=>"53"}
  • {"month"=>"10", "year"=>"2015", "pdf_views"=>"18", "xml_views"=>"0", "html_views"=>"68"}
  • {"month"=>"11", "year"=>"2015", "pdf_views"=>"21", "xml_views"=>"0", "html_views"=>"52"}
  • {"month"=>"12", "year"=>"2015", "pdf_views"=>"15", "xml_views"=>"0", "html_views"=>"56"}
  • {"month"=>"1", "year"=>"2016", "pdf_views"=>"9", "xml_views"=>"0", "html_views"=>"42"}
  • {"month"=>"2", "year"=>"2016", "pdf_views"=>"11", "xml_views"=>"0", "html_views"=>"43"}
  • {"month"=>"3", "year"=>"2016", "pdf_views"=>"14", "xml_views"=>"0", "html_views"=>"51"}
  • {"month"=>"4", "year"=>"2016", "pdf_views"=>"13", "xml_views"=>"0", "html_views"=>"55"}
  • {"month"=>"5", "year"=>"2016", "pdf_views"=>"4", "xml_views"=>"0", "html_views"=>"19"}
  • {"month"=>"6", "year"=>"2016", "pdf_views"=>"29", "xml_views"=>"0", "html_views"=>"39"}
  • {"month"=>"7", "year"=>"2016", "pdf_views"=>"7", "xml_views"=>"0", "html_views"=>"21"}
  • {"month"=>"8", "year"=>"2016", "pdf_views"=>"5", "xml_views"=>"0", "html_views"=>"28"}
  • {"month"=>"9", "year"=>"2016", "pdf_views"=>"9", "xml_views"=>"0", "html_views"=>"38"}
  • {"month"=>"10", "year"=>"2016", "pdf_views"=>"15", "xml_views"=>"0", "html_views"=>"43"}
  • {"month"=>"11", "year"=>"2016", "pdf_views"=>"4", "xml_views"=>"0", "html_views"=>"38"}
  • {"month"=>"12", "year"=>"2016", "pdf_views"=>"27", "xml_views"=>"1", "html_views"=>"52"}
  • {"month"=>"1", "year"=>"2017", "pdf_views"=>"7", "xml_views"=>"0", "html_views"=>"34"}
  • {"month"=>"2", "year"=>"2017", "pdf_views"=>"8", "xml_views"=>"0", "html_views"=>"29"}
  • {"month"=>"3", "year"=>"2017", "pdf_views"=>"12", "xml_views"=>"0", "html_views"=>"23"}
  • {"month"=>"4", "year"=>"2017", "pdf_views"=>"20", "xml_views"=>"0", "html_views"=>"48"}
  • {"month"=>"5", "year"=>"2017", "pdf_views"=>"12", "xml_views"=>"1", "html_views"=>"44"}
  • {"month"=>"6", "year"=>"2017", "pdf_views"=>"11", "xml_views"=>"0", "html_views"=>"27"}
  • {"month"=>"7", "year"=>"2017", "pdf_views"=>"8", "xml_views"=>"0", "html_views"=>"23"}
  • {"month"=>"8", "year"=>"2017", "pdf_views"=>"5", "xml_views"=>"0", "html_views"=>"12"}
  • {"month"=>"9", "year"=>"2017", "pdf_views"=>"5", "xml_views"=>"1", "html_views"=>"32"}
  • {"month"=>"10", "year"=>"2017", "pdf_views"=>"8", "xml_views"=>"1", "html_views"=>"23"}
  • {"month"=>"11", "year"=>"2017", "pdf_views"=>"7", "xml_views"=>"1", "html_views"=>"36"}
  • {"month"=>"12", "year"=>"2017", "pdf_views"=>"3", "xml_views"=>"0", "html_views"=>"32"}
  • {"month"=>"1", "year"=>"2018", "pdf_views"=>"9", "xml_views"=>"0", "html_views"=>"16"}
  • {"month"=>"2", "year"=>"2018", "pdf_views"=>"7", "xml_views"=>"0", "html_views"=>"9"}
  • {"month"=>"3", "year"=>"2018", "pdf_views"=>"10", "xml_views"=>"0", "html_views"=>"15"}
  • {"month"=>"4", "year"=>"2018", "pdf_views"=>"5", "xml_views"=>"0", "html_views"=>"13"}
  • {"month"=>"5", "year"=>"2018", "pdf_views"=>"7", "xml_views"=>"1", "html_views"=>"8"}
  • {"month"=>"6", "year"=>"2018", "pdf_views"=>"5", "xml_views"=>"1", "html_views"=>"9"}
  • {"month"=>"7", "year"=>"2018", "pdf_views"=>"11", "xml_views"=>"3", "html_views"=>"23"}
  • {"month"=>"8", "year"=>"2018", "pdf_views"=>"6", "xml_views"=>"1", "html_views"=>"15"}
  • {"month"=>"9", "year"=>"2018", "pdf_views"=>"3", "xml_views"=>"0", "html_views"=>"8"}
  • {"month"=>"10", "year"=>"2018", "pdf_views"=>"6", "xml_views"=>"1", "html_views"=>"7"}
  • {"month"=>"11", "year"=>"2018", "pdf_views"=>"10", "xml_views"=>"0", "html_views"=>"17"}
  • {"month"=>"12", "year"=>"2018", "pdf_views"=>"4", "xml_views"=>"0", "html_views"=>"8"}
  • {"month"=>"1", "year"=>"2019", "pdf_views"=>"2", "xml_views"=>"0", "html_views"=>"10"}
  • {"month"=>"2", "year"=>"2019", "pdf_views"=>"5", "xml_views"=>"0", "html_views"=>"4"}
  • {"month"=>"3", "year"=>"2019", "pdf_views"=>"4", "xml_views"=>"4", "html_views"=>"7"}
  • {"month"=>"4", "year"=>"2019", "pdf_views"=>"6", "xml_views"=>"0", "html_views"=>"12"}
  • {"month"=>"5", "year"=>"2019", "pdf_views"=>"6", "xml_views"=>"0", "html_views"=>"12"}
  • {"month"=>"6", "year"=>"2019", "pdf_views"=>"4", "xml_views"=>"1", "html_views"=>"5"}

Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1608855", "https://ndownloader.figshare.com/files/1608856", "https://ndownloader.figshare.com/files/1608857", "https://ndownloader.figshare.com/files/1608858", "https://ndownloader.figshare.com/files/1608859"], "description"=>"<div><p>The epidermal growth factor receptor (EGFR) plays a key role in regulating cell proliferation, migration, and differentiation, and aberrant EGFR signaling is implicated in a variety of cancers. EGFR signaling is triggered by extracellular ligand binding, which promotes EGFR dimerization and activation. Ligand-binding measurements are consistent with a negatively cooperative model in which the ligand-binding affinity at either binding site in an EGFR dimer is weaker when the other site is occupied by a ligand. This cooperativity is widely believed to be central to the effects of ligand concentration on EGFR-mediated intracellular signaling. Although the extracellular portion of the human EGFR dimer has been resolved crystallographically, the crystal structures do not reveal the structural origin of this negative cooperativity, which has remained unclear. Here we report the results of molecular dynamics simulations suggesting that asymmetrical interactions of the two binding sites with the membrane may be responsible (perhaps along with other factors) for this negative cooperativity. In particular, in our simulations the extracellular domains of an EGFR dimer spontaneously lay down on the membrane in an orientation in which favorable membrane contacts were made with one of the bound ligands, but could not be made with the other. Similar interactions were observed when EGFR was glycosylated, as it is in vivo.</p></div>", "links"=>[], "tags"=>["biophysics", "Computational biology", "bound", "ligands", "contributes", "binding", "cooperativity", "egf"], "article_id"=>1117440, "categories"=>["Biological Sciences"], "users"=>["Anton Arkhipov", "Yibing Shan", "Eric T. Kim", "David E. Shaw"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1003742.s001", "https://dx.doi.org/10.1371/journal.pcbi.1003742.s002", "https://dx.doi.org/10.1371/journal.pcbi.1003742.s003", "https://dx.doi.org/10.1371/journal.pcbi.1003742.s004", "https://dx.doi.org/10.1371/journal.pcbi.1003742.s005"], "stats"=>{"downloads"=>6, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Membrane_Interaction_of_Bound_Ligands_Contributes_to_the_Negative_Binding_Cooperativity_of_the_EGF_Receptor_/1117440", "title"=>"Membrane Interaction of Bound Ligands Contributes to the Negative Binding Cooperativity of the EGF Receptor", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-07-24 04:04:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/1608839"], "description"=>"<p>(A) Snapshots from the endpoints of the simulations. The ectodomain dimers lie down on the membrane surface in a variety of ways; in each case, however, only one of the two ligands establishes strong interactions with the membrane. (B) The free energy of each ligand's interaction with its host receptor in a two-ligand EGFR dimer (upper panels) estimated using MM/GBVI, the strength of its interaction with the membrane bilayer (middle panels) estimated in the same way, and the distance between its N-terminus and the membrane (lower panels) in three independent simulations. In the middle panels, the surface area of each ligand buried by the membrane is plotted. As shown, the membrane-facing ligand (blue) enjoys greater binding free energy, and thus higher binding affinity, than the solvent-facing one (red) due to the additional energy conferred by the membrane interaction.</p>", "links"=>[], "tags"=>["biophysics", "Computational biology", "simulations", "two-ligand", "egfr"], "article_id"=>1117425, "categories"=>["Biological Sciences"], "users"=>["Anton Arkhipov", "Yibing Shan", "Eric T. Kim", "David E. Shaw"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003742.g005", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ligand_membrane_interaction_in_simulations_of_the_two_ligand_EGFR_dimer_/1117425", "title"=>"Ligand-membrane interaction in simulations of the two-ligand EGFR dimer.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-24 04:04:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/1608842"], "description"=>"<p>(A) The staggered and flush conformations <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003742#pcbi.1003742-Liu1\" target=\"_blank\">[20]</a> are observed in PDB entries 1IVO and 1MOX, respectively. These two conformations are shown at the top and in the middle. At the bottom, the yellow subunits of both crystal structures are superposed and the view is from above (relative to the other two images). The conformations can be distinguished by the angle <i>θ</i> formed by the Cα atoms of Ile190 and Pro204 of one subunit and Pro204 of the other. (B) Distributions of <i>θ</i> observed in simulations of the one- (black) and two-ligand (red) EGFR dimers. Data from the simulations of ectodomains in solution, reported in ref. <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003742#pcbi.1003742-Arkhipov1\" target=\"_blank\">[26]</a>, and data from simulations of nonglycosylated and glycosylated EGFR constructs with the membrane, which are reported in the present study, are shown from top to bottom, respectively. Values of <i>θ</i> from the crystal structures are indicated. Two slightly different <i>θ</i> values are obtained for each crystal structure, because the structures are not exactly symmetric; the spaces between these values are shown as colored bands.</p>", "links"=>[], "tags"=>["biophysics", "Computational biology", "conformations", "extracellular"], "article_id"=>1117428, "categories"=>["Biological Sciences"], "users"=>["Anton Arkhipov", "Yibing Shan", "Eric T. Kim", "David E. Shaw"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003742.g006", "stats"=>{"downloads"=>3, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_8220_Staggered_8221_and_8220_flush_8221_conformations_of_the_extracellular_dimers_/1117428", "title"=>"“Staggered” and “flush” conformations of the extracellular dimers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-24 04:04:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/1608823"], "description"=>"<p>(A) A schematic description of EGFR ligand binding. The basic scheme is taken from ref. <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003742#pcbi.1003742-Macdonald1\" target=\"_blank\">[15]</a>, but we have color coded the ligands to distinguish the free, the membrane-facing bound, and the solvent-facing bound ligands according to the simulation findings. “L” and “K” are used to denote the association constants of EGFR dimerization and ligand binding, respectively. The negative cooperativity is reflected in K<sub>21</sub>≫K<sub>22</sub>. The ligands bound to monomers are assumed to face the membrane as found in previous simulations of EGFR monomers (ref. <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003742#pcbi.1003742-Arkhipov1\" target=\"_blank\">[26]</a>; see the <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003742#s3\" target=\"_blank\">Discussion</a>). (B–D) Simulation of an EGFR dimer construct consisting of the ectodomains and TM helices. One EGFR subunit is colored in shades of blue, the other in shades of red, and the two bound EGF ligands in yellow. In the initial state (B), the ectodomain dimer is standing upright, perpendicular to the membrane. In the course of the simulation, the ectodomain dimer approaches the membrane (C), permitting the formation of extensive interactions between one of the ligands and the membrane, resulting in the partial-resting orientation. The EGF side chains Pro7 and Leu8 (orange) penetrate deep into the membrane, reaching the lipid tails (inset). Later in the course of the simulation (D), the ectodomain dimer approaches closer to the membrane and lies flat on its surface, in the full-resting orientation. (E) The free energy of each ligand's interaction with its host receptor (EGF1, blue; EGF2, red) in a two-ligand EGFR dimer (left panel) and of its interaction with the membrane bilayer (right panel); calculations used the MM/GBVI method. (F) The N-terminal sequences of EGF in various vertebrate species and from a set of members of the human EGF family. The amino acids shown correspond to residues 1–10 of human EGF. The conserved Cys6 is marked in gray and hydrophobic residues in positions 1–8 are marked in orange. Hydrophobic and aromatic residues beyond position 8 are expected to be buried in the protein interior.</p>", "links"=>[], "tags"=>["biophysics", "Computational biology", "ectodomain", "egfr", "dimer", "lying"], "article_id"=>1117413, "categories"=>["Biological Sciences"], "users"=>["Anton Arkhipov", "Yibing Shan", "Eric T. Kim", "David E. Shaw"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003742.g001", "stats"=>{"downloads"=>2, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_ectodomain_portion_of_the_EGFR_dimer_lying_on_the_membrane_/1117413", "title"=>"The ectodomain portion of the EGFR dimer lying on the membrane.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-24 04:04:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/1608831"], "description"=>"<p>(A) A fully glycosylated ectodomain dimer of EGFR. The BiS1F1, Man8, and Man6 glycans attached to EGFR are colored by atom type (gray for carbon, red for oxygen, and blue for nitrogen). (B) The conformation at the end of the simulation shown from two opposite directions. (C) Distance between the N terminus of each ligand (blue, membrane-facing ligand; red, solvent-facing ligand) and the membrane surface (see <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003742#s4\" target=\"_blank\">Methods</a>) in the glycosylated-EGFR simulation, and total surface area of the ligand buried due to its interactions with the receptor and the membrane (left panels). Also shown are the results of the MM/GBVI calculations of the free energy of each ligand's interaction with its host receptor in the glycosylated two-ligand EGFR dimer (middle panel) and the results of similar calculations for each ligand's interaction with the membrane bilayer (the right panel). The membrane-facing ligand enjoys greater binding free energy, and thus higher binding affinity, than the solvent-facing one due to the additional energy conferred by the membrane interaction.</p>", "links"=>[], "tags"=>["biophysics", "Computational biology", "glycosylated"], "article_id"=>1117417, "categories"=>["Biological Sciences"], "users"=>["Anton Arkhipov", "Yibing Shan", "Eric T. Kim", "David E. Shaw"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003742.g002", "stats"=>{"downloads"=>2, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Simulation_of_fully_glycosylated_EGFR_/1117417", "title"=>"Simulation of fully glycosylated EGFR.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-24 04:04:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/1608834"], "description"=>"<p>(A) The conformation of the one-ligand ectodomain dimer obtained from a simulation employing the crystal structure of the two-ligand dimer (PDB entry 3NJP; ref. <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003742#pcbi.1003742-Lu1\" target=\"_blank\">[23]</a>), with the ligand removed from the red subunit, as a starting state. Domains I–IV and the EGF molecule are marked. The one-ligand dimer differs from the two-ligand dimer in the conformation of the domain IV of the red subunit. (B) The one-ligand dimer lying down on the membrane. The ligand bound to this dimer faces the membrane. Snapshots from simulations of the nonglycosylated and glycosylated dimers are shown. (C) The free energy of a ligand's interaction with its host receptor in a one-ligand EGFR dimer (upper panels) estimated using MM/GBVI, the strength of its interaction with the membrane bilayer (middle panels) estimated in the same way, and the distance between the ligand's N-terminus and the membrane (lower panels) in three independent simulations in which the receptors were not glycosylated and in one additional simulation in which they were. Also shown (middle panels) is the total surface area of the ligand buried due to its interactions with the receptor and the membrane. As indicated by these data, the additional free energy conferred by the ligand's membrane interaction is a significant fraction of its interaction energy with the receptor.</p>", "links"=>[], "tags"=>["biophysics", "Computational biology", "one-ligand"], "article_id"=>1117420, "categories"=>["Biological Sciences"], "users"=>["Anton Arkhipov", "Yibing Shan", "Eric T. Kim", "David E. Shaw"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003742.g003", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Simulations_of_the_one_ligand_dimer_/1117420", "title"=>"Simulations of the one-ligand dimer.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-24 04:04:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/1608837"], "description"=>"<p>(A) The two subunits of the ectodomain dimer, as observed at the end of one of the simulations without glycosylation (left) and at the end of the simulation with full glycosylation (right), superimposed using the Cα atoms of domains I–III for reference. The EGFR ectodomains I–III are shown in blue and red, and the EGF molecules bound to them are shown in yellow and orange, respectively. (B) Domain II maintaining the same conformation in both subunits of the two-ligand EGFR dimer. Angle <i>Φ</i> (the angle formed by Cα atoms of residues 194, 239, and 296 in EGFR, or 189, 235, and 289 in dEGFR) characterizes the bending of domain II. This angle is different in each of the two subunits of the asymmetric two-ligand dEGFR dimer (the solid and dashed black lines; PDB entry 3LTF). The average angles in the simulations of two- and one-ligand EGFR dimers (<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003742#pcbi-1003742-g002\" target=\"_blank\">Figs. 2</a>, <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003742#pcbi-1003742-g003\" target=\"_blank\">3</a>, and <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1003742#pcbi-1003742-g005\" target=\"_blank\">5</a>; labels refer to nonglycosylated EGFR simulations 1, 2, and 3, and glycosylated EGFR simulation G) are shown for each of the two subunits in blue and red (error bars correspond to the standard deviation). The angle <i>Φ</i> is illustrated in the schematic of domains I, II, and III of EGFR on the right.</p>", "links"=>[], "tags"=>["biophysics", "Computational biology", "two-ligand", "ectodomain", "dimer", "symmetric"], "article_id"=>1117423, "categories"=>["Biological Sciences"], "users"=>["Anton Arkhipov", "Yibing Shan", "Eric T. Kim", "David E. Shaw"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003742.g004", "stats"=>{"downloads"=>3, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_two_ligand_ectodomain_dimer_remaining_symmetric_in_the_simulations_/1117423", "title"=>"The two-ligand ectodomain dimer remaining symmetric in the simulations.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-07-24 04:04:26"}

PMC Usage Stats | Further Information

  • {"unique-ip"=>"3", "full-text"=>"1", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"7"}
  • {"unique-ip"=>"27", "full-text"=>"26", "pdf"=>"11", "abstract"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"14", "supp-data"=>"17", "cited-by"=>"0", "year"=>"2014", "month"=>"8"}
  • {"unique-ip"=>"25", "full-text"=>"15", "pdf"=>"14", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"9", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2014", "month"=>"9"}
  • {"unique-ip"=>"16", "full-text"=>"15", "pdf"=>"7", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"5", "cited-by"=>"0", "year"=>"2014", "month"=>"10"}
  • {"unique-ip"=>"11", "full-text"=>"11", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"4", "cited-by"=>"0", "year"=>"2014", "month"=>"11"}
  • {"unique-ip"=>"6", "full-text"=>"7", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"12"}
  • {"unique-ip"=>"13", "full-text"=>"12", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"1"}
  • {"unique-ip"=>"23", "full-text"=>"20", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"2"}
  • {"unique-ip"=>"12", "full-text"=>"11", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"11", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"3"}
  • {"unique-ip"=>"8", "full-text"=>"10", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"10", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"4"}
  • {"unique-ip"=>"12", "full-text"=>"12", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"5"}
  • {"unique-ip"=>"7", "full-text"=>"6", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"6"}
  • {"unique-ip"=>"7", "full-text"=>"9", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"7"}
  • {"unique-ip"=>"10", "full-text"=>"8", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"8"}
  • {"unique-ip"=>"9", "full-text"=>"8", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"9"}
  • {"unique-ip"=>"5", "full-text"=>"3", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"10"}
  • {"unique-ip"=>"19", "full-text"=>"11", "pdf"=>"10", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2015", "month"=>"11"}
  • {"unique-ip"=>"9", "full-text"=>"8", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"12"}
  • {"unique-ip"=>"5", "full-text"=>"5", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"1"}
  • {"unique-ip"=>"8", "full-text"=>"6", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"2"}
  • {"unique-ip"=>"10", "full-text"=>"8", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"3"}
  • {"unique-ip"=>"7", "full-text"=>"8", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2016", "month"=>"4"}
  • {"unique-ip"=>"2", "full-text"=>"2", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"5"}
  • {"unique-ip"=>"7", "full-text"=>"7", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"6"}
  • {"unique-ip"=>"10", "full-text"=>"7", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2016", "month"=>"7"}
  • {"unique-ip"=>"2", "full-text"=>"3", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"8"}
  • {"unique-ip"=>"11", "full-text"=>"12", "pdf"=>"6", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"9"}
  • {"unique-ip"=>"9", "full-text"=>"7", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2016", "month"=>"10"}
  • {"unique-ip"=>"7", "full-text"=>"5", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"11"}
  • {"unique-ip"=>"5", "full-text"=>"5", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"12"}
  • {"unique-ip"=>"9", "full-text"=>"7", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"1"}
  • {"unique-ip"=>"1", "full-text"=>"0", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"2"}
  • {"unique-ip"=>"4", "full-text"=>"5", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"3"}
  • {"unique-ip"=>"3", "full-text"=>"3", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"4"}
  • {"unique-ip"=>"7", "full-text"=>"7", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"5"}
  • {"unique-ip"=>"5", "full-text"=>"4", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"6"}
  • {"unique-ip"=>"2", "full-text"=>"3", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"7"}
  • {"unique-ip"=>"3", "full-text"=>"3", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"8"}
  • {"unique-ip"=>"4", "full-text"=>"4", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"9"}
  • {"unique-ip"=>"13", "full-text"=>"9", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"5", "cited-by"=>"0", "year"=>"2017", "month"=>"10"}
  • {"unique-ip"=>"9", "full-text"=>"9", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"11"}
  • {"unique-ip"=>"4", "full-text"=>"4", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"12"}
  • {"unique-ip"=>"6", "full-text"=>"9", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2018", "month"=>"1"}
  • {"unique-ip"=>"3", "full-text"=>"3", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"3"}
  • {"unique-ip"=>"6", "full-text"=>"4", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2019", "month"=>"1"}
  • {"unique-ip"=>"4", "full-text"=>"4", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"5"}
  • {"unique-ip"=>"1", "full-text"=>"1", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"4"}
  • {"unique-ip"=>"6", "full-text"=>"7", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"6"}
  • {"unique-ip"=>"8", "full-text"=>"9", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2018", "month"=>"7"}
  • {"unique-ip"=>"6", "full-text"=>"6", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"8"}
  • {"unique-ip"=>"7", "full-text"=>"7", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"9"}
  • {"unique-ip"=>"4", "full-text"=>"4", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"10"}
  • {"unique-ip"=>"10", "full-text"=>"9", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2018", "month"=>"11"}
  • {"unique-ip"=>"8", "full-text"=>"7", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2018", "month"=>"12"}
  • {"unique-ip"=>"2", "full-text"=>"3", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"3", "full-text"=>"3", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
  • {"unique-ip"=>"6", "full-text"=>"3", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}

Relative Metric

{"start_date"=>"2014-01-01T00:00:00Z", "end_date"=>"2014-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences", "average_usage"=>[291]}, {"subject_area"=>"/Biology and life sciences/Cell biology", "average_usage"=>[286]}, {"subject_area"=>"/Physical sciences/Physics", "average_usage"=>[266]}]}
Loading … Spinner
There are currently no alerts