Towards a Molecular Understanding of the Link between Imatinib Resistance and Kinase Conformational Dynamics
Publication Date
November 25, 2015
Journal
PLOS Computational Biology
Authors
Silvia Lovera, Maria Morando, Encarna Pucheta Martinez, Jorge L. Martinez Torrecuadrada, et al
Volume
11
Issue
11
Pages
e1004578
DOI
https://dx.plos.org/10.1371/journal.pcbi.1004578
Publisher URL
http://journals.plos.org/ploscompbiol/article?id=10.1371%2Fjournal.pcbi.1004578
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/26606374
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659586
Europe PMC
http://europepmc.org/abstract/MED/26606374
Web of Science
000365801600036
Scopus
84949294800
Mendeley
http://www.mendeley.com/research/towards-molecular-understanding-link-between-imatinib-resistance-kinase-conformational-dynamics
Events
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Mendeley | Further Information

{"title"=>"Towards a Molecular Understanding of the Link between Imatinib Resistance and Kinase Conformational Dynamics", "type"=>"journal", "authors"=>[{"first_name"=>"Silvia", "last_name"=>"Lovera", "scopus_author_id"=>"54960413000"}, {"first_name"=>"Maria", "last_name"=>"Morando", "scopus_author_id"=>"56992663300"}, {"first_name"=>"Encarna", "last_name"=>"Pucheta-Martinez", "scopus_author_id"=>"56993986800"}, {"first_name"=>"Jorge L.", "last_name"=>"Martinez-Torrecuadrada", "scopus_author_id"=>"6602524724"}, {"first_name"=>"Giorgio", "last_name"=>"Saladino", "scopus_author_id"=>"23978674400"}, {"first_name"=>"Francesco L.", "last_name"=>"Gervasio", "scopus_author_id"=>"6603509498"}], "year"=>2015, "source"=>"PLoS Computational Biology", "identifiers"=>{"doi"=>"10.1371/journal.pcbi.1004578", "scopus"=>"2-s2.0-84949294800", "pui"=>"607184194", "issn"=>"15537358", "pmid"=>"26606374", "sgr"=>"84949294800"}, "id"=>"b8a7b1bf-420e-3066-8917-ec7359ca339c", "abstract"=>"Due to its inhibition of the Abl kinase domain in the BCR-ABL fusion protein, imatinib is strikingly effective in the initial stage of chronic myeloid leukemia with more than 90% of the patients showing complete remission. However, as in the case of most targeted anti-cancer therapies, the emergence of drug resistance is a serious concern. Several drug-resistant mutations affecting the catalytic domain of Abl and other tyrosine kinases are now known. But, despite their importance and the adverse effect that they have on the prognosis of the cancer patients harboring them, the molecular mechanism of these mutations is still debated. Here by using long molecular dynamics simulations and large-scale free energy calculations complemented by in vitro mutagenesis and microcalorimetry experiments, we model the effect of several widespread drug-resistant mutations of Abl. By comparing the conformational free energy landscape of the mutants with those of the wild-type tyrosine kinases we clarify their mode of action. It involves significant and complex changes in the inactive-to-active dynamics and entropy/enthalpy balance of two functional elements: the activation-loop and the conserved DFG motif. What is more the T315I gatekeeper mutant has a significant impact on the binding mechanism itself and on the binding kinetics.", "link"=>"http://www.mendeley.com/research/towards-molecular-understanding-link-between-imatinib-resistance-kinase-conformational-dynamics", "reader_count"=>35, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Researcher"=>12, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>2, "Student > Master"=>1, "Other"=>1, "Student > Bachelor"=>5, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Researcher"=>12, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>2, "Student > Master"=>1, "Other"=>1, "Student > Bachelor"=>5, "Professor"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>7, "Agricultural and Biological Sciences"=>11, "Medicine and Dentistry"=>1, "Physics and Astronomy"=>3, "Chemistry"=>9, "Psychology"=>1, "Computer Science"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Chemistry"=>{"Chemistry"=>9}, "Physics and Astronomy"=>{"Physics and Astronomy"=>3}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>11}, "Computer Science"=>{"Computer Science"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>7}}, "reader_count_by_country"=>{"Brazil"=>1, "United Kingdom"=>1, "Italy"=>1, "Croatia"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2577460"], "description"=>"<p>The main structural features, including the regions undergoing conformational changes are highlighted in different colors (a). On the right (b) imatinib binding mode and the position of drug-resistant mutants are shown. The mutants with a “known” mechanism of action are depicted in green, those for which the mechanism is still unknown in red.</p>", "links"=>[], "tags"=>["binding kinetics", "mutation", "imatinib resistance", "Kinase Conformational Dynamics", "T 315I gatekeeper", "Drug Resistance", "cancer patients", "tyrosine kinases", "ABL kinase domain", "dynamics simulations", "Myeloid leukemia", "microcalorimetry experiments", "DFG motif", "energy calculations", "binding mechanism", "energy landscape"], "article_id"=>1612616, "categories"=>["Uncategorised"], "users"=>["Silvia Lovera", "Maria Morando", "Encarna Pucheta-Martinez", "Jorge L. Martínez-Torrecuadrada", "Giorgio Saladino", "Francesco L. Gervasio"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004578.g001", "stats"=>{"downloads"=>4, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Abl_structure_and_location_of_drug_resistant_mutations_/1612616", "title"=>"Abl structure and location of drug-resistant mutations.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-11-25 03:24:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/2577464"], "description"=>"<p>(a) RMSF of Abl and Src. Fluctuations of the N-lobe (left) and of the A-loop (right) for the Abl mutants (b). and the TKs (c). Shades of red and blue identify strong and weak binders, respectively. Dotted lines are used for clarity.</p>", "links"=>[], "tags"=>["binding kinetics", "mutation", "imatinib resistance", "Kinase Conformational Dynamics", "T 315I gatekeeper", "Drug Resistance", "cancer patients", "tyrosine kinases", "ABL kinase domain", "dynamics simulations", "Myeloid leukemia", "microcalorimetry experiments", "DFG motif", "energy calculations", "binding mechanism", "energy landscape"], "article_id"=>1612617, "categories"=>["Uncategorised"], "users"=>["Silvia Lovera", "Maria Morando", "Encarna Pucheta-Martinez", "Jorge L. Martínez-Torrecuadrada", "Giorgio Saladino", "Francesco L. Gervasio"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004578.g002", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Root_mean_square_fluctuation_analysis_of_TKs_and_Abl_resistant_mutants_/1612617", "title"=>"Root mean square fluctuation analysis of TKs and Abl resistant mutants.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-11-25 03:24:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/2577471"], "description"=>"<p>Free energy surfaces of Abl, Src (adapted from Ref. [<a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004578#pcbi.1004578.ref029\" target=\"_blank\">29</a>]), and Abl drug-resistant mutants projected on the distances between DFG Asp<sub>404</sub> and Lys<sub>295</sub> (CV1) and DFG Phe<sub>405</sub> and Ile<sub>293</sub> (Leu<sub>137</sub> in Src) (CV2). The free energy minima corresponding to DFG-in conformations are labeled “IN”, while “OUT” correspond to DFG-out conformations. The contour lines are drawn every 1 kcal/mol.</p>", "links"=>[], "tags"=>["binding kinetics", "mutation", "imatinib resistance", "Kinase Conformational Dynamics", "T 315I gatekeeper", "Drug Resistance", "cancer patients", "tyrosine kinases", "ABL kinase domain", "dynamics simulations", "Myeloid leukemia", "microcalorimetry experiments", "DFG motif", "energy calculations", "binding mechanism", "energy landscape"], "article_id"=>1612620, "categories"=>["Uncategorised"], "users"=>["Silvia Lovera", "Maria Morando", "Encarna Pucheta-Martinez", "Jorge L. Martínez-Torrecuadrada", "Giorgio Saladino", "Francesco L. Gervasio"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004578.g003", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Free_energy_of_the_DFG_flip_transition_/1612620", "title"=>"Free energy of the DFG flip transition.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-11-25 03:24:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/2577476"], "description"=>"<p>Free energy surfaces of Abl, Src, and drug-resistant mutants projected on the optimal path describing the conformational change of the A-loop from open to closed in Src (CV1) and Abl (CV2). The free energy minima corresponding to an extended A-loop active-like conformation are labeled “A”, “B” is used for A-loop semi-closed (inactive) conformations and “C” for fully closed A-loop conformations. The contour lines are drawn every 1 kcal/mol.</p>", "links"=>[], "tags"=>["binding kinetics", "mutation", "imatinib resistance", "Kinase Conformational Dynamics", "T 315I gatekeeper", "Drug Resistance", "cancer patients", "tyrosine kinases", "ABL kinase domain", "dynamics simulations", "Myeloid leukemia", "microcalorimetry experiments", "DFG motif", "energy calculations", "binding mechanism", "energy landscape"], "article_id"=>1612622, "categories"=>["Uncategorised"], "users"=>["Silvia Lovera", "Maria Morando", "Encarna Pucheta-Martinez", "Jorge L. Martínez-Torrecuadrada", "Giorgio Saladino", "Francesco L. Gervasio"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004578.g004", "stats"=>{"downloads"=>3, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Free_energy_of_the_A_loop_opening_/1612622", "title"=>"Free energy of the A-loop opening.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-11-25 03:24:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/2577483"], "description"=>"<p>Free energy surfaces associated to the binding of imatinib to WT Abl (top panel) and the T315I Abl “gatekeeper” mutant (bottom panel). The deepest energy minima correspond to the crystallographic binding pose and are labeled A. On the way out, B and B’ correspond to an intermediate state (metastable in WT Abl) where imatinib is in between the DFG and the <i>α</i>C helix. States C and C’ correspond to the “external binding pose”. Interestingly in Abl T315I there are two exit channels and both have an higher barrier than in the WT. The contour lines are drawn every 2 kcal/mol.</p>", "links"=>[], "tags"=>["binding kinetics", "mutation", "imatinib resistance", "Kinase Conformational Dynamics", "T 315I gatekeeper", "Drug Resistance", "cancer patients", "tyrosine kinases", "ABL kinase domain", "dynamics simulations", "Myeloid leukemia", "microcalorimetry experiments", "DFG motif", "energy calculations", "binding mechanism", "energy landscape"], "article_id"=>1612625, "categories"=>["Uncategorised"], "users"=>["Silvia Lovera", "Maria Morando", "Encarna Pucheta-Martinez", "Jorge L. Martínez-Torrecuadrada", "Giorgio Saladino", "Francesco L. Gervasio"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004578.g005", "stats"=>{"downloads"=>4, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Free_energy_of_imatinib_un_binding_to_Abl_and_to_the_T315I_8216_gatekeeper_8217_mutant_/1612625", "title"=>"Free energy of imatinib (un-)binding to Abl and to the T315I ‘gatekeeper’ mutant.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-11-25 03:24:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/2577484"], "description"=>"<p>RMSF of the A-loop region and IC<sub>50</sub> values of imatinib for the studied tyrosine kinases and the designed triple mutants of Src.</p>", "links"=>[], "tags"=>["binding kinetics", "mutation", "imatinib resistance", "Kinase Conformational Dynamics", "T 315I gatekeeper", "Drug Resistance", "cancer patients", "tyrosine kinases", "ABL kinase domain", "dynamics simulations", "Myeloid leukemia", "microcalorimetry experiments", "DFG motif", "energy calculations", "binding mechanism", "energy landscape"], "article_id"=>1612626, "categories"=>["Uncategorised"], "users"=>["Silvia Lovera", "Maria Morando", "Encarna Pucheta-Martinez", "Jorge L. Martínez-Torrecuadrada", "Giorgio Saladino", "Francesco L. Gervasio"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004578.t001", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_RMSF_of_the_A_loop_region_and_IC_50_values_of_imatinib_for_the_studied_tyrosine_kinases_and_the_designed_triple_mutants_of_Src_/1612626", "title"=>"RMSF of the A-loop region and IC<sub>50</sub> values of imatinib for the studied tyrosine kinases and the designed triple mutants of Src.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-11-25 03:24:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/2577486"], "description"=>"<p>The RMSF values have been averaged from MD simulations.</p>", "links"=>[], "tags"=>["binding kinetics", "mutation", "imatinib resistance", "Kinase Conformational Dynamics", "T 315I gatekeeper", "Drug Resistance", "cancer patients", "tyrosine kinases", "ABL kinase domain", "dynamics simulations", "Myeloid leukemia", "microcalorimetry experiments", "DFG motif", "energy calculations", "binding mechanism", "energy landscape"], "article_id"=>1612627, "categories"=>["Uncategorised"], "users"=>["Silvia Lovera", "Maria Morando", "Encarna Pucheta-Martinez", "Jorge L. Martínez-Torrecuadrada", "Giorgio Saladino", "Francesco L. Gervasio"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004578.t002", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_K_d_for_the_Src_mutants_Abl_and_Src_WT_/1612627", "title"=>"K<sub>d</sub> for the Src mutants, Abl and Src WT.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-11-25 03:24:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/2577487"], "description"=>"<p>Entropy and Enthalpy contributions to the DFG-in DFG-out flip as obtained from the linear regression of the Free Energy as a function of temperature.</p>", "links"=>[], "tags"=>["binding kinetics", "mutation", "imatinib resistance", "Kinase Conformational Dynamics", "T 315I gatekeeper", "Drug Resistance", "cancer patients", "tyrosine kinases", "ABL kinase domain", "dynamics simulations", "Myeloid leukemia", "microcalorimetry experiments", "DFG motif", "energy calculations", "binding mechanism", "energy landscape"], "article_id"=>1612628, "categories"=>["Uncategorised"], "users"=>["Silvia Lovera", "Maria Morando", "Encarna Pucheta-Martinez", "Jorge L. Martínez-Torrecuadrada", "Giorgio Saladino", "Francesco L. Gervasio"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1004578.t003", "stats"=>{"downloads"=>6, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Entropy_and_Enthalpy_contributions_to_the_DFG_in_DFG_out_flip_as_obtained_from_the_linear_regression_of_the_Free_Energy_as_a_function_of_temperature_/1612628", "title"=>"Entropy and Enthalpy contributions to the DFG-in DFG-out flip as obtained from the linear regression of the Free Energy as a function of temperature.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-11-25 03:24:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/2577552", "https://ndownloader.figshare.com/files/2577553", "https://ndownloader.figshare.com/files/2577554", "https://ndownloader.figshare.com/files/2577555", "https://ndownloader.figshare.com/files/2577557", "https://ndownloader.figshare.com/files/2577558", "https://ndownloader.figshare.com/files/2577559", "https://ndownloader.figshare.com/files/2577560", "https://ndownloader.figshare.com/files/2577561", "https://ndownloader.figshare.com/files/2577562", "https://ndownloader.figshare.com/files/2577563", "https://ndownloader.figshare.com/files/2577564", "https://ndownloader.figshare.com/files/2577565", "https://ndownloader.figshare.com/files/2577566", "https://ndownloader.figshare.com/files/2577567", "https://ndownloader.figshare.com/files/2577568", "https://ndownloader.figshare.com/files/2577569", "https://ndownloader.figshare.com/files/2577570"], "description"=>"<div><p>Due to its inhibition of the Abl kinase domain in the BCR-ABL fusion protein, imatinib is strikingly effective in the initial stage of chronic myeloid leukemia with more than 90% of the patients showing complete remission. However, as in the case of most targeted anti-cancer therapies, the emergence of drug resistance is a serious concern. Several drug-resistant mutations affecting the catalytic domain of Abl and other tyrosine kinases are now known. But, despite their importance and the adverse effect that they have on the prognosis of the cancer patients harboring them, the molecular mechanism of these mutations is still debated. Here by using long molecular dynamics simulations and large-scale free energy calculations complemented by <i>in vitro</i> mutagenesis and microcalorimetry experiments, we model the effect of several widespread drug-resistant mutations of Abl. By comparing the conformational free energy landscape of the mutants with those of the wild-type tyrosine kinases we clarify their mode of action. It involves significant and complex changes in the inactive-to-active dynamics and entropy/enthalpy balance of two functional elements: the activation-loop and the conserved DFG motif. What is more the T315I gatekeeper mutant has a significant impact on the binding mechanism itself and on the binding kinetics.</p></div>", "links"=>[], "tags"=>["binding kinetics", "mutation", "imatinib resistance", "Kinase Conformational Dynamics", "T 315I gatekeeper", "Drug Resistance", "cancer patients", "tyrosine kinases", "ABL kinase domain", "dynamics simulations", "Myeloid leukemia", "microcalorimetry experiments", "DFG motif", "energy calculations", "binding mechanism", "energy landscape"], "article_id"=>1612629, "categories"=>["Uncategorised"], "users"=>["Silvia Lovera", "Maria Morando", "Encarna Pucheta-Martinez", "Jorge L. Martínez-Torrecuadrada", "Giorgio Saladino", "Francesco L. Gervasio"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1004578.s001", "https://dx.doi.org/10.1371/journal.pcbi.1004578.s002", "https://dx.doi.org/10.1371/journal.pcbi.1004578.s003", "https://dx.doi.org/10.1371/journal.pcbi.1004578.s004", "https://dx.doi.org/10.1371/journal.pcbi.1004578.s005", "https://dx.doi.org/10.1371/journal.pcbi.1004578.s006", "https://dx.doi.org/10.1371/journal.pcbi.1004578.s007", "https://dx.doi.org/10.1371/journal.pcbi.1004578.s008", "https://dx.doi.org/10.1371/journal.pcbi.1004578.s009", "https://dx.doi.org/10.1371/journal.pcbi.1004578.s010", "https://dx.doi.org/10.1371/journal.pcbi.1004578.s011", "https://dx.doi.org/10.1371/journal.pcbi.1004578.s012", "https://dx.doi.org/10.1371/journal.pcbi.1004578.s013", "https://dx.doi.org/10.1371/journal.pcbi.1004578.s014", "https://dx.doi.org/10.1371/journal.pcbi.1004578.s015", "https://dx.doi.org/10.1371/journal.pcbi.1004578.s016", "https://dx.doi.org/10.1371/journal.pcbi.1004578.s017", "https://dx.doi.org/10.1371/journal.pcbi.1004578.s018"], "stats"=>{"downloads"=>19, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Towards_a_Molecular_Understanding_of_the_Link_between_Imatinib_Resistance_and_Kinase_Conformational_Dynamics_/1612629", "title"=>"Towards a Molecular Understanding of the Link between Imatinib Resistance and Kinase Conformational Dynamics", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-11-25 03:24:58"}

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{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
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