Mechanisms of allostery and membrane attachment in Ras GTPases: implications for anti-cancer drug discovery

Current Medicinal Chemistry
Alemayehu A Gorfe

Abstract

Ras GTPases are membrane-anchored molecular switches that mediate signaling pathways controlling a variety of cellular processes, including cell division and development. Despite their prominent role in many forms of cancer, little is known about the structure of the membrane bound protein or the mechanism and thermodynamics of membrane insertion. The modulation of membrane binding by the catalytic domain is another area of on-going scrutiny. Recent computational and experimental efforts that have begun to shed some light on these issues are the subject of this review. The bulk of the available structural and thermodynamic information on membrane-bound Ras has been obtained by studying peptides derived from the membrane-anchoring regions of N-ras and H-ras proteins. However, those results have been complemented by data, though limited, on the membrane binding of the full-length Ras as well as by predictions about putative communication routes between the GTP-hydrolyzing catalytic domain and the membrane-interacting C-terminus. A tentative mechanistic picture of Ras signaling that is emerging from these studies will be discussed in connection with allostery and implication for the design of selective anti-cancer drugs.

Citations

Sep 22, 2012·Journal of the American Chemical Society·Zhenlong LiAlemayehu A Gorfe
Feb 24, 2012·PLoS Computational Biology·Priyanka PrakashAlemayehu A Gorfe
Nov 3, 2011·PloS One·Barry J GrantAlemayehu A Gorfe
Sep 29, 2011·Journal of Molecular Biology·Greg BuhrmanCarla Mattos
Oct 22, 2015·Acta Biochimica Et Biophysica Sinica·Michael McCarthyAlemayehu A Gorfe
Oct 17, 2015·Angewandte Chemie·Philipp M CrommHerbert Waldmann
Aug 3, 2013·Biochimica Et Biophysica Acta·Priyanka Prakash, Alemayehu A Gorfe
Jan 1, 2014·Molecular Simulation·Priyanka Prakash, Alemayehu A Gorfe
Oct 28, 2015·PLoS Computational Biology·Priyanka PrakashAlemayehu A Gorfe
Jul 12, 2016·Chemical Society Reviews·Shaoyong LuRuth Nussinov
Oct 7, 2008·Free Radical Biology & Medicine·Vellareddy AnantharamAnumantha G Kanthasamy
Mar 3, 2017·Journal of Chemical Theory and Computation·Abdallah Sayyed-Ahmad, Alemayehu A Gorfe
Jun 7, 2018·PloS One·Ammu Prasanna Kumar, Suryani Lukman
Nov 14, 2015·Journal of Immunoassay & Immunochemistry·Cristiana TanaseMonica Neagu
Aug 24, 2019·Small GTPases·Alemayehu A Gorfe, Kwang-Jin Cho
Sep 16, 2020·Physical Chemistry Chemical Physics : PCCP·Jianzhong ChenWeiliang Zhu
Mar 25, 2019·Chemical Biology & Drug Design·Amit K GuptaAlemayehu A Gorfe
Nov 5, 2019·Biochimica Et Biophysica Acta. Molecular Cell Research·Imran KhanJohn P O'Bryan
Oct 12, 2010·Journal of Chemical Theory and Computation·Lorant Janosi, Alemayehu A Gorfe
Sep 27, 2019·The Journal of Physical Chemistry. B·Priyanka Prakash, Alemayehu A Gorfe

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