7RP4

Crystal structure of KRAS G12C in complex with GNE-1952

Summary for 7RP4

• Entry DOI: 10.2210/pdb7rp4/pdb
• Descriptor: Isoform 2B of GTPase KRas, 1-[4-[6-chloranyl-7-(5-methyl-1~{H}-indazol-4-yl)quinazolin-4-yl]piperazin-1-yl]propan-1-one, GUANOSINE-5'-DIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: gtpase, inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 40514.28

Authors

Oh, A.,Tam, C.,Wang, W. (deposition date: 2021-08-03, release date: 2022-03-16, Last modification date: 2024-12-25)

Primary citation

Davies, C.W.,Oh, A.J.,Mroue, R.,Steffek, M.,Bruning, J.M.,Xiao, Y.,Feng, S.,Jayakar, S.,Chan, E.,Arumugam, V.,Uribe, S.C.,Drummond, J.,Frommlet, A.,Lu, C.,Franke, Y.,Merchant, M.,Koeppen, H.,Quinn, J.G.,Malhotra, S.,Do, S.,Gazzard, L.,Purkey, H.E.,Rudolph, J.,Mulvihill, M.M.,Koerber, J.T.,Wang, W.,Evangelista, M.
Conformation-locking antibodies for the discovery and characterization of KRAS inhibitors.
Nat.Biotechnol., 40:769-778, 2022

PubMed Abstract: Small molecules that stabilize inactive protein conformations are an underutilized strategy for drugging dynamic or otherwise intractable proteins. To facilitate the discovery and characterization of such inhibitors, we created a screening platform to identify conformation-locking antibodies for molecular probes (CLAMPs) that distinguish and induce rare protein conformational states. Applying the approach to KRAS, we discovered CLAMPs that recognize the open conformation of KRAS stabilized by covalent inhibitors. One CLAMP enables the visualization of KRAS covalent modification in vivo and can be used to investigate response heterogeneity to KRAS inhibitors in patient tumors. A second CLAMP enhances the affinity of weak ligands binding to the KRAS switch II region (SWII) by stabilizing a specific conformation of KRAS, thereby enabling the discovery of such ligands that could serve as leads for the development of drugs in a high-throughput screen. We show that combining the complementary properties of antibodies and small molecules facilitates the study and drugging of dynamic proteins.

PubMed: 34992247
DOI: 10.1038/s41587-021-01126-9

Experimental method

X-RAY DIFFRACTION (2.15 Å)