ORCID Profile
0000-0003-3065-1456
Current Organisation
University of California, San Diego
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Publisher: American Chemical Society (ACS)
Date: 31-01-2007
DOI: 10.1021/JM061053F
Abstract: Ras proteins regulate signal transduction processes that control cell growth and proliferation. Their disregulation is a common cause of human tumors. Atomic level structural and dynamical information in a membrane environment is crucial for understanding signaling specificity among Ras isoforms and for the design of selective anti-cancer agents. Here, the structure of the full-length H-Ras protein in complex with a 1,2-dimyristoylglycero-3-phosphocholine (DMPC) bilayer obtained from modeling and all-atom explicit solvent molecular dynamics simulations, as well as experimental validation of the main results, are presented. We find that, in addition to the lipid anchor, H-Ras membrane binding involves direct interaction of residues in the catalytic domain with DMPC phosphates. Two modes of binding (possibly modulated by GTP/GDP exchange) differing in the orientation and bilayer contact of the soluble domain as well as in the participation of the flexible linker in membrane binding are proposed. These results are supported by our initial in vivo experiments. The overall structures of the protein and the bilayer remain similar to those of the isolated components, with few localized structural and dynamical changes. The implications of the results to membrane lateral segregation and other aspects of Ras signaling are discussed.
Publisher: Proceedings of the National Academy of Sciences
Date: 06-09-2016
Abstract: Chemical ersity has recently risen as key structural feature for the discovery of novel selective drugs of G protein-coupled receptors (GPCRs). However, the traditional drug discovery technique of combinatorial chemistry coupled to high-throughput screening has become less attractive because of its immense financial impact. To address this problem, we implemented a computer-aided drug design approach, using the M 2 muscarinic acetylcholine receptor (mAChR) as a GPCR model, and performed computational enhanced s ling simulations to account for the receptor flexibility. Through iterative molecular docking and experimental testing, half of the 38 computationally selected National Cancer Institute compounds were validated as allosteric modulators of the M 2 mAChR. Our method successfully identified positive and negative allosteric modulators of M 2 mAChR with unprecedented chemical ersity.
Publisher: American Chemical Society (ACS)
Date: 13-09-2010
DOI: 10.1021/JM100331D
Publisher: Wiley
Date: 14-02-2008
Publisher: Springer New York
Date: 24-11-2012
Publisher: American Chemical Society (ACS)
Date: 31-07-2009
DOI: 10.1021/BI900712R
Publisher: Wiley
Date: 09-2012
Location: United States of America
No related grants have been discovered for J. Andrew McCammon.