Identification of Potential Small Molecule Binding Pockets on Rho Family GTPases
Publication Date
July 16, 2012
Journal
PLOS ONE
Authors
Juan Manuel Ortiz Sanchez, Sara E. Nichols, Jacqueline Sayyah, Joan Heller Brown, et al
Volume
7
Issue
7
Pages
e40809
DOI
https://dx.plos.org/10.1371/journal.pone.0040809
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0040809
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/22815826
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3397943
Europe PMC
http://europepmc.org/abstract/MED/22815826
Web of Science
000306466100071
Scopus
84864018934
Mendeley
http://www.mendeley.com/research/identification-potential-small-molecule-binding-pockets-rho-family-gtpases-6
Events
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Mendeley | Further Information

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Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/609075"], "description"=>"<p>Compounds were selected from a pocket directed virtual screen and tested on Glioblastoma cells (1321N1). Cells were pre-treated for 1 hr with either DMSO control or 30 µM of compound 157767, 335504, 25740 or 2561 and subsequently stimulated for 15 minutes with either vehicle or 0.5 U/mL thrombin. RhoA activity was assessed via pull-down by rhotekin and total RhoA was determined using an anti-RhoA antibody. Bar graph shows densitometric results from 4 independent experiments. Data are presented as means ± SEM; *P<0.001 vs. vehicle control, one-way ANOVA.</p>", "links"=>[], "tags"=>["rho", "compounds", "inhibit", "thrombin", "stimulated", "rhoa", "activation", "glioblastoma"], "article_id"=>279555, "categories"=>["Biochemistry", "Biological Sciences", "Chemistry", "Information And Computing Sciences", "Biophysics"], "users"=>["Juan Manuel Ortiz-Sanchez", "Sara E. Nichols", "Jacqueline Sayyah", "Joan Heller Brown", "J. Andrew McCammon", "Barry J. Grant"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040809.g008", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Putative_Rho_compounds_inhibit_thrombin_stimulated_RhoA_activation_in_glioblastoma_cells_/279555", "title"=>"Putative Rho compounds inhibit thrombin stimulated RhoA activation in glioblastoma cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-16 02:39:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/608845"], "description"=>"<p>The projection of (A) cMD and (B) aMD conformers onto the first two principal components of the crystallographic ensemble. The distribution of simulated conformers is depicted with density-shaded red, green and blue points for the GTP, GDP and APO simulations respectively. Crystal structures conformations are in black (see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040809#pone-0040809-g002\" target=\"_blank\"><b>Figure 2</b></a> and main text for details).</p>", "links"=>[], "tags"=>["sampling", "accelerated", "molecular"], "article_id"=>279332, "categories"=>["Biochemistry", "Biological Sciences", "Chemistry", "Information And Computing Sciences", "Biophysics"], "users"=>["Juan Manuel Ortiz-Sanchez", "Sara E. Nichols", "Jacqueline Sayyah", "Joan Heller Brown", "J. Andrew McCammon", "Barry J. Grant"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040809.g006", "stats"=>{"downloads"=>1, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Conformational_sampling_in_conventional_and_accelerated_molecular_dynamics_simulations_/279332", "title"=>"Conformational sampling in conventional and accelerated molecular dynamics simulations.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-16 02:35:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/608939"], "description"=>"<p>(A) results from the ensemble of crystal structures, (B) the combined GTP cMD conformers, (C) the combined cMD conformers and (D) the single aMD trajectory conformers. The protein structure of reference corresponds to the RhoA-GDP complex from <i>Homo Sapiens</i> (PDB code 1FTN).</p>", "links"=>[], "tags"=>["probe", "occupancy"], "article_id"=>279433, "categories"=>["Biochemistry", "Biological Sciences", "Chemistry", "Information And Computing Sciences", "Biophysics"], "users"=>["Juan Manuel Ortiz-Sanchez", "Sara E. Nichols", "Jacqueline Sayyah", "Joan Heller Brown", "J. Andrew McCammon", "Barry J. Grant"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040809.g007", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Absolute_probe_occupancy_results_from_fragment_mapping_analysis_/279433", "title"=>"Absolute probe occupancy results from fragment mapping analysis.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-16 02:37:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/317462", "https://ndownloader.figshare.com/files/317493", "https://ndownloader.figshare.com/files/317513", "https://ndownloader.figshare.com/files/317537", "https://ndownloader.figshare.com/files/317565"], "description"=>"<div><p>Rho GTPases are conformational switches that control a wide variety of signaling pathways critical for eukaryotic cell development and proliferation. They represent attractive targets for drug design as their aberrant function and deregulated activity is associated with many human diseases including cancer. Extensive high-resolution structures (>100) and recent mutagenesis studies have laid the foundation for the design of new structure-based chemotherapeutic strategies. Although the inhibition of Rho signaling with drug-like compounds is an active area of current research, very little attention has been devoted to directly inhibiting Rho by targeting potential allosteric non-nucleotide binding sites. By avoiding the nucleotide binding site, compounds may minimize the potential for undesirable off-target interactions with other ubiquitous GTP and ATP binding proteins. Here we describe the application of molecular dynamics simulations, principal component analysis, sequence conservation analysis, and ensemble small-molecule fragment mapping to provide an extensive mapping of potential small-molecule binding pockets on Rho family members. Characterized sites include novel pockets in the vicinity of the conformationaly responsive switch regions as well as distal sites that appear to be related to the conformations of the nucleotide binding region. Furthermore the use of accelerated molecular dynamics simulation, an advanced sampling method that extends the accessible time-scale of conventional simulations, is found to enhance the characterization of novel binding sites when conformational changes are important for the protein mechanism.</p> </div>", "links"=>[], "tags"=>["binding", "pockets", "rho", "gtpases"], "article_id"=>122668, "categories"=>["Biochemistry", "Biological Sciences", "Chemistry", "Information And Computing Sciences", "Biophysics"], "users"=>["Juan Manuel Ortiz-Sanchez", "Sara E. Nichols", "Jacqueline Sayyah", "Joan Heller Brown", "J. Andrew McCammon", "Barry J. Grant"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0040809.s001", "https://dx.doi.org/10.1371/journal.pone.0040809.s002", "https://dx.doi.org/10.1371/journal.pone.0040809.s003", "https://dx.doi.org/10.1371/journal.pone.0040809.s004", "https://dx.doi.org/10.1371/journal.pone.0040809.s005"], "stats"=>{"downloads"=>3, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Identification_of_Potential_Small_Molecule_Binding_Pockets_on_Rho_Family_GTPases/122668", "title"=>"Identification of Potential Small Molecule Binding Pockets on Rho Family GTPases", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-07-16 00:44:28"}
  • {"files"=>["https://ndownloader.figshare.com/files/608561"], "description"=>"<p>(A) Fragment probe occupancy per position in Rho across all available structures. (B) Sequence conservation entropy scores for a 21-letter alphabet (20 amino acids and a gap, in black) and 7-letter alphabet (where amino acids are grouped into six classes based on their physicochemical properties, in light gray). (C) The mean (black) and maximum (light gray) solvent exposure per position in all structures. (D) Flexibility per position in terms of RMSF (bars) and mean <i>B</i>-factor (line) over all structures. Major elements of secondary structure (shaded rectangles) and positions with a high degree of sequence conservation (red ticks) are indicated in the marginal areas of each plot to facilitate comparison. Both the secondary structure and residue numbering are according to the RhoA-GDP complex from <i>Homo Sapiens</i> (PDB code 1FTN).</p>", "links"=>[], "tags"=>["binding", "characterization", "crystallographic"], "article_id"=>279054, "categories"=>["Biochemistry", "Biological Sciences", "Chemistry", "Information And Computing Sciences", "Biophysics"], "users"=>["Juan Manuel Ortiz-Sanchez", "Sara E. Nichols", "Jacqueline Sayyah", "Joan Heller Brown", "J. Andrew McCammon", "Barry J. Grant"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040809.g003", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Fragment_binding_site_characterization_in_the_crystallographic_dataset_/279054", "title"=>"Fragment binding site characterization in the crystallographic dataset.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-16 02:30:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/608406"], "description"=>"<p>Conformer plot of available Rho GTPase crystal structures projected in the planes defined by the two most significant principal components (termed PC1 and PC2, see insert). Crystallographic GTP structures are colored red, GDP green, and nucleotide free gray. Inset: Eigenvalue spectrum: results obtained from diagonalisation of the covariance matrix of aligned atom coordinates from the Rho crystal structures. The magnitude of each eigenvalue is expressed as the percentage of the total variance (mean square fluctuation) captured by the corresponding eigenvector. Labels indicate the cumulative sum of the proportion of the total variance accounted for in all preceding eigenvectors.</p>", "links"=>[], "tags"=>["pca", "rho"], "article_id"=>278898, "categories"=>["Biochemistry", "Biological Sciences", "Chemistry", "Information And Computing Sciences", "Biophysics"], "users"=>["Juan Manuel Ortiz-Sanchez", "Sara E. Nichols", "Jacqueline Sayyah", "Joan Heller Brown", "J. Andrew McCammon", "Barry J. Grant"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040809.g002", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Results_of_PCA_on_Rho_crystal_structures_/278898", "title"=>"Results of PCA on Rho crystal structures.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-16 02:28:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/608760"], "description"=>"<p>The probe occupancy for the ensemble of crystal structures (gray) and the <b>A</b> combined conventional molecular dynamics (cMD) conformers (orange), and <b>B</b> an individual cMD GTP trajectory (red). Blue and green squares at the bottom of each plot highlight those residues that are involved in a binding pocket only in the crystal structure data set (blue) or the trajectory dataset (green). <b>C</b> Binding site positions found in cMD that are not observed in any crystallographic structure, see text for details.</p>", "links"=>[], "tags"=>["binding", "molecular"], "article_id"=>279256, "categories"=>["Biochemistry", "Biological Sciences", "Chemistry", "Information And Computing Sciences", "Biophysics"], "users"=>["Juan Manuel Ortiz-Sanchez", "Sara E. Nichols", "Jacqueline Sayyah", "Joan Heller Brown", "J. Andrew McCammon", "Barry J. Grant"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040809.g005", "stats"=>{"downloads"=>0, "page_views"=>31, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Probe_binding_results_from_conventional_molecular_dynamics_simulations_/279256", "title"=>"Probe binding results from conventional molecular dynamics simulations.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-16 02:34:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/608668"], "description"=>"<p>(A) Comparison of the absolute probe occupancy per position between GDP/GTP and (B) GDP/APO structure sets. Probe occupancies are colored in red, green and blue for GTP, GDP and APO states. Dashed lines indicate positions in the nucleotide binding site. Orange squares indicate residues with statistically significant differences in probe occupancy (<i>p</i><0.05) between each structure set. Major elements of secondary structure (shaded rectangles) are indicated in the marginal top areas of each plot. (C) Increasing colored radii representation of the absolute probe occupancy per residue in the GTP, GDP and APO crystal structure ensembles.</p>", "links"=>[], "tags"=>["differences", "probe"], "article_id"=>279161, "categories"=>["Biochemistry", "Biological Sciences", "Chemistry", "Information And Computing Sciences", "Biophysics"], "users"=>["Juan Manuel Ortiz-Sanchez", "Sara E. Nichols", "Jacqueline Sayyah", "Joan Heller Brown", "J. Andrew McCammon", "Barry J. Grant"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040809.g004", "stats"=>{"downloads"=>0, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Nucleotide_state_associated_differences_in_probe_occupancy_/279161", "title"=>"Nucleotide state associated differences in probe occupancy.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-16 02:32:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/608319"], "description"=>"<p>(A) Schematic representation of the Rho GTPase activation cycle. (1) The GTP-bound active state is generated by guanine exchange factors (GEFs), promoting the exchange of GDP for GTP. (2) GTPases activating proteins (GAPs) catalyze the hydrolysis of GTP to GDP, restoring the GDP-bound inactive state. (3) Stabilization of the GDP-bound inactive state by GDP dissociation inhibitors (GDIs). (B) The molecular structure of representative the GTP and GDP-bound Rho conformations (PDB codes: 1KMQ and 1FTN). The switch regions of the GTP-bound form are shown in red and GDP-bound form in green.</p>", "links"=>[], "tags"=>["gtpase"], "article_id"=>278811, "categories"=>["Biochemistry", "Biological Sciences", "Chemistry", "Information And Computing Sciences", "Biophysics"], "users"=>["Juan Manuel Ortiz-Sanchez", "Sara E. Nichols", "Jacqueline Sayyah", "Joan Heller Brown", "J. Andrew McCammon", "Barry J. Grant"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040809.g001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Rho_GTPase_activation_/278811", "title"=>"Rho GTPase activation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-16 02:26:51"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"15", "full-text"=>"17", "pdf"=>"9", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"9", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2012", "month"=>"10"}
  • {"unique-ip"=>"8", "full-text"=>"8", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2012", "month"=>"12"}
  • {"unique-ip"=>"12", "full-text"=>"12", "pdf"=>"4", "abstract"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"1"}
  • {"unique-ip"=>"16", "full-text"=>"14", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"11", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"3"}
  • {"unique-ip"=>"13", "full-text"=>"13", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"2"}
  • {"unique-ip"=>"11", "full-text"=>"18", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"4"}
  • {"unique-ip"=>"13", "full-text"=>"12", "pdf"=>"6", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2012", "month"=>"11"}
  • {"unique-ip"=>"8", "full-text"=>"7", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"5"}
  • {"unique-ip"=>"12", "full-text"=>"13", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"9", "supp-data"=>"5", "cited-by"=>"0", "year"=>"2013", "month"=>"6"}
  • {"unique-ip"=>"12", "full-text"=>"9", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"5", "cited-by"=>"0", "year"=>"2013", "month"=>"7"}
  • {"unique-ip"=>"4", "full-text"=>"4", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2013", "month"=>"8"}
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  • {"unique-ip"=>"9", "full-text"=>"7", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"5"}
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  • {"unique-ip"=>"4", "full-text"=>"8", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"8"}
  • {"unique-ip"=>"3", "full-text"=>"12", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"9"}
  • {"unique-ip"=>"6", "full-text"=>"15", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2015", "month"=>"10"}
  • {"unique-ip"=>"13", "full-text"=>"35", "pdf"=>"6", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"4", "cited-by"=>"0", "year"=>"2014", "month"=>"7"}
  • {"unique-ip"=>"4", "full-text"=>"1", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"8"}
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  • {"unique-ip"=>"10", "full-text"=>"4", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2014", "month"=>"10"}
  • {"unique-ip"=>"4", "full-text"=>"3", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"2"}
  • {"unique-ip"=>"14", "full-text"=>"10", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2014", "month"=>"11"}
  • {"unique-ip"=>"9", "full-text"=>"17", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2014", "month"=>"12"}
  • {"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"=>"2015", "month"=>"1"}
  • {"unique-ip"=>"9", "full-text"=>"19", "pdf"=>"6", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"11"}
  • {"unique-ip"=>"4", "full-text"=>"4", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"12"}
  • {"unique-ip"=>"6", "full-text"=>"4", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"1"}
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Relative Metric

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