Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization
Yibing Shan,Michael P. Eastwood,Xuewu Zhang,Eric T. Kim,Anton Arkhipov,Ron O. Dror,John M. Jumper,John Kuriyan,David E. Shaw,David E. Shaw +9 more
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TLDR
Using long-timescale molecular dynamics simulations, it is found that the N lobe dimerization interface of the wild-type EGFR kinase domain is intrinsically disordered and that it becomes ordered only uponDimerization.About:
This article is published in Cell.The article was published on 2012-05-11 and is currently open access. It has received 309 citations till now. The article focuses on the topics: Receptor tyrosine kinase & Gefitinib.read more
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Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways.
Ping Wee,Zhixiang Wang +1 more
TL;DR: The molecular mechanisms that regulate EGFR signal transduction are reviewed, including the EGFR structure and its mutations, ligand binding and EGFR dimerization, as well as the signaling pathways that lead to G1 cell cycle progression.
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Role of Molecular Dynamics and Related Methods in Drug Discovery.
TL;DR: The theoretical background of MD and enhanced sampling methods is reviewed, focusing on free-energy perturbation, metadynamics, steered MD, and other methods most consistently used to study drug-target binding.
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EGF receptor trafficking: consequences for signaling and cancer.
TL;DR: This data indicates that EGF receptor endocytic traffic can regulate signaling and cell survival and EGFR traffic promoted by antineoplastic therapy is important in tumor resistance.
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Allostery in Disease and in Drug Discovery
TL;DR: This work focuses on the challenging questions of how allostery can both cause disease and contribute to development of new therapeutics and aims to increase the awareness of the linkage between disease symptoms on the cellular level and specific aberrant allosteric actions on the molecular level.
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Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors
Yong Jia,Cai-Hong Yun,Eun Young Park,Dalia Ercan,Mari Manuia,Jose Juarez,Chunxiao Xu,Kevin Rhee,Ting Chen,Haikuo Zhang,Sangeetha Palakurthi,Jaebong Jang,Gerald Lelais,Michael DiDonato,Badry Bursulaya,Pierre-Yves Michellys,Robert Epple,Thomas H. Marsilje,Matthew McNeill,Wenshuo Lu,Jennifer L. Harris,Bender Steven Lee,Kwok-Kin Wong,Pasi A. Jänne,Michael J. Eck +24 more
TL;DR: Rational discovery of EAI045 is described, an allosteric inhibitor that targets selected drug-resistant EGFR mutants but spares the wild type receptor and shows dramatic synergy of cetuximab, an antibody therapeutic that blocks EGFR dimerization, rendering the kinase uniformly susceptible to theAllosteric agent.
References
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Comparison of simple potential functions for simulating liquid water
TL;DR: In this article, the authors compared the Bernal Fowler (BF), SPC, ST2, TIPS2, TIP3P, and TIP4P potential functions for liquid water in the NPT ensemble at 25°C and 1 atm.
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Canonical dynamics: Equilibrium phase-space distributions
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Development and testing of a general amber force field.
TL;DR: A general Amber force field for organic molecules is described, designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most organic and pharmaceutical molecules that are composed of H, C, N, O, S, P, and halogens.
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Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib
Thomas J. Lynch,Daphne W. Bell,Raffaella Sordella,Sarada Gurubhagavatula,Ross A. Okimoto,Brian W. Brannigan,Patricia L. Harris,Sara M. Haserlat,Jeffrey G. Supko,Frank G. Haluska,David N. Louis,David C. Christiani,Jeff Settleman,Daniel A. Haber +13 more
TL;DR: A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib, and these mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor.
Journal ArticleDOI
EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.
J. Guillermo Paez,Pasi A. Jänne,Pasi A. Jänne,Jeffrey C. Lee,Sean Tracy,Heidi Greulich,Heidi Greulich,Stacey Gabriel,Paula Herman,Frederic J. Kaye,Neal I. Lindeman,Titus J. Boggon,Katsuhiko Naoki,Hidefumini Sasaki,Yoshitaka Fujii,Michael J. Eck,William R. Sellers,William R. Sellers,William R. Sellers,Bruce E. Johnson,Bruce E. Johnson,Matthew Meyerson,Matthew Meyerson +22 more
TL;DR: Results suggest that EGFR mutations may predict sensitivity to gefitinib, and treatment with the EGFR kinase inhibitor gefitsinib causes tumor regression in some patients with NSCLC, more frequently in Japan.
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J. Guillermo Paez,Pasi A. Jänne,Pasi A. Jänne,Jeffrey C. Lee,Sean Tracy,Heidi Greulich,Heidi Greulich,Stacey Gabriel,Paula Herman,Frederic J. Kaye,Neal I. Lindeman,Titus J. Boggon,Katsuhiko Naoki,Hidefumini Sasaki,Yoshitaka Fujii,Michael J. Eck,William R. Sellers,William R. Sellers,William R. Sellers,Bruce E. Johnson,Bruce E. Johnson,Matthew Meyerson,Matthew Meyerson +22 more