Dimerization-driven activation of the intracellular kinase domains of the epidermal growth factor receptor (EGFR) upon extracellular ligand binding is crucial to cellular pathways regulating proliferation, migration, and differentiation. Inactive EGFR can exist as both monomers and dimers, suggesting that the mechanism regulating EGFR activity may be subtle. The membrane itself may play a role but creates substantial difficulties for structural studies. Our molecular dynamics simulations of membrane-embedded EGFR suggest that, in ligand-bound dimers, the extracellular domains assume conformations favoring dimerization of the transmembrane helices near their N termini, dimerization of the juxtamembrane segments, and formation of asymmetric (active) kinase dimers. In ligand-free dimers, by holding apart the N termini of the transmembrane helices, the extracellular domains instead favor C-terminal dimerization of the transmembrane helices, juxtamembrane segment dissociation and membrane burial, and formation of symmetric (inactive) kinase dimers. Electrostatic interactions of EGFR’s intracellular module with the membrane are critical in maintaining this coupling.
第一篇的通讯作者，也是第二篇的作者： David E. Shaw 也是Desmond（Schordinger 软件包里动力学模块）的作者之一。
David E. Shaw
作者实验室http://www.deshawresearch.com/chiefscientist.html David E. Shaw serves as Chief Scientist of D. E. Shaw Research and as a Senior Research Fellow at the Center for Computational Biology and Bioinformatics at Columbia University. He received his Ph.D. from Stanford University in 1980, served on the faculty of the Computer Science Department at Columbia until 1986, and founded the D. E. Shaw group in 1988. Since 2001, Dr. Shaw has devoted his time to hands-on research in the field of computational biochemistry. Although he leads the lab’s research efforts in his role as Chief Scientist, his focus is largely technical, with limited involvement in operational and administrative management. Dr. Shaw was appointed to the President's Council of Advisors on Science and Technology by President Clinton in 1994, and again by President Obama in 2009. He is a member of the National Academy of Engineering, and is a fellow of the American Academy of Arts and Sciences and of the American Association for the Advancement of Science.
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发表于 2013-3-14 14:26:27
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发表于 2013-3-14 14:53:09
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