Linked Life Data

21717480

Source:http://linkedlifedata.com/resource/pubmed/id/21717480

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
13
pubmed:dateCreated
2011-7-22
pubmed:abstractText
The epidermal growth factor receptor (EGFR) is a major target for drugs in treating lung carcinoma as it promotes cell growth and tumor progression. Structural studies have demonstrated that EGFR exists in an equilibrium between catalytically active and inactive forms, and dramatic conformational transitions occur during its activation. It is known that EGFR mutations promote such conformational changes that affect its activation and drug efficacy. The most common point mutation in lung cancer patients is a leucine to arginine substitution at amino acid 834 (L834R). In a recent article, we have studied changes in drug binding affinities due to cancer mutations of EGFR using ensemble molecular dynamics (MD) simulations. Here, we address an enhanced activation mechanism thought to be associated with this mutation. Using extended timescale MD simulations, the structural and energetic properties are studied for both active and inactive conformations of EGFR. The thermodynamic stabilities of these two conformations are characterized by free energy landscapes estimated from molecular mechanics/Poisson-Boltzmann solvent area calculations. Our study reveals that the L834R mutation introduces conformational changes in both states, adjusting the relative stabilities of active and inactive conformations and hence the activation of the EGFR kinase.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
1096-987X
pubmed:author
pubmed:copyrightInfo
Copyright © 2011 Wiley Periodicals, Inc.
pubmed:issnType
Electronic
pubmed:volume
32
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2843-52
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
Molecular dynamics simulation reveals structural and thermodynamic features of kinase activation by cancer mutations within the epidermal growth factor receptor.
pubmed:affiliation
Department of Chemistry, Centre for Computational Science, University College London, London WC1H 0AJ, United Kingdom.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't