کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2184953 | 1095951 | 2011 | 17 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Analysis of Binding Site Hot Spots on the Surface of Ras GTPase Analysis of Binding Site Hot Spots on the Surface of Ras GTPase](/preview/png/2184953.png)
We have recently discovered an allosteric switch in Ras, bringing an additional level of complexity to this GTPase whose mutants are involved in nearly 30% of cancers. Upon activation of the allosteric switch, there is a shift in helix 3/loop 7 associated with a disorder to order transition in the active site. Here, we use a combination of multiple solvent crystal structures and computational solvent mapping (FTMap) to determine binding site hot spots in the “off” and “on” allosteric states of the GTP-bound form of H-Ras. Thirteen sites are revealed, expanding possible target sites for ligand binding well beyond the active site. Comparison of FTMaps for the H and K isoforms reveals essentially identical hot spots. Furthermore, using NMR measurements of spin relaxation, we determined that K-Ras exhibits global conformational dynamics very similar to those we previously reported for H-Ras. We thus hypothesize that the global conformational rearrangement serves as a mechanism for allosteric coupling between the effector interface and remote hot spots in all Ras isoforms. At least with respect to the binding sites involving the G domain, H-Ras is an excellent model for K-Ras and probably N-Ras as well. Ras has so far been elusive as a target for drug design. The present work identifies various unexplored hot spots throughout the entire surface of Ras, extending the focus from the disordered active site to well-ordered locations that should be easier to target.
► We explore the surface of Ras GTPase to identify areas for small-molecule binding.
► Ras has two lobes that we coin the effector lobe and the allosteric lobe.
► Binding sites at interlobal region are poised to modulate an allosteric switch.
► The global dynamics of H-Ras and K-Ras isoforms are very similar.
► We identify new sights at the Ras/membrane interface likely to be druggable.
Journal: Journal of Molecular Biology - Volume 413, Issue 4, 4 November 2011, Pages 773–789