8TLR

Crystal Structure of human HRAS G12C covalently bound to AMG 510

Summary for 8TLR

• Entry DOI: 10.2210/pdb8tlr/pdb
• Descriptor: GTPase HRas, GUANOSINE-5'-DIPHOSPHATE, AMG 510 (bound form), ... (5 entities in total)
• Functional Keywords: hras, h-ras, sotorasib, ras, oncoprotein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 19951.40

Authors

Morstein, J.,Guiley, K.Z.,Shokat, K.M. (deposition date: 2023-07-27, release date: 2024-07-31, Last modification date: 2024-11-20)

Primary citation

Morstein, J.,Bowcut, V.,Fernando, M.,Yang, Y.,Zhu, L.,Jenkins, M.L.,Evans, J.T.,Guiley, K.Z.,Peacock, D.M.,Krahnke, S.,Lin, Z.,Taran, K.A.,Huang, B.J.,Stephen, A.G.,Burke, J.E.,Lightstone, F.C.,Shokat, K.M.
Targeting Ras-, Rho-, and Rab-family GTPases via a conserved cryptic pocket.
Cell, 187:6379-, 2024

PubMed Abstract: The family of Ras-like GTPases consists of over 150 different members, regulated by an even larger number of guanine exchange factors (GEFs) and GTPase-activating proteins (GAPs) that comprise cellular switch networks that govern cell motility, growth, polarity, protein trafficking, and gene expression. Efforts to develop selective small molecule probes and drugs for these proteins have been hampered by the high affinity of guanosine triphosphate (GTP) and lack of allosteric regulatory sites. This paradigm was recently challenged by the discovery of a cryptic allosteric pocket in the switch II region of K-Ras. Here, we ask whether similar pockets are present in GTPases beyond K-Ras. We systematically surveyed members of the Ras, Rho, and Rab family of GTPases and found that many GTPases exhibit targetable switch II pockets. Notable differences in the composition and conservation of key residues offer potential for the development of optimized inhibitors for many members of this previously undruggable family.

PubMed: 39255801
DOI: 10.1016/j.cell.2024.08.017

Experimental method

X-RAY DIFFRACTION (1.70003947485 Å)