4M22

Crystal Structure of small molecule acrylamide 16 covalently bound to K-Ras G12C

Summary for 4M22

• Entry DOI: 10.2210/pdb4m22/pdb
• Related: 4L8G 4L9S 4L9W 4LPK 4LRW 4LUC 4LV6 4LYF 4LYH 4LYJ 4M1O 4M1S 4M1T 4M1W 4M1Y 4M21
• Descriptor: K-Ras GTPase, MAGNESIUM ION, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: gtpase, gdp bound, small molecule inhibitor, covalent binder, signaling protein-inhibitor complex, signaling protein/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane ; Lipid-anchor ; Cytoplasmic side : P01116
• Total number of polymer chains: 3
• Total formula weight: 60151.32

Authors

Ostrem, J.M.,Peters, U.,Sos, M.L.,Wells, J.A.,Shokat, K.M. (deposition date: 2013-08-05, release date: 2013-11-27, Last modification date: 2024-10-30)

Primary citation

Ostrem, J.M.,Peters, U.,Sos, M.L.,Wells, J.A.,Shokat, K.M.
K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions.
Nature, 503:548-551, 2013

PubMed Abstract: Somatic mutations in the small GTPase K-Ras are the most common activating lesions found in human cancer, and are generally associated with poor response to standard therapies. Efforts to target this oncogene directly have faced difficulties owing to its picomolar affinity for GTP/GDP and the absence of known allosteric regulatory sites. Oncogenic mutations result in functional activation of Ras family proteins by impairing GTP hydrolysis. With diminished regulation by GTPase activity, the nucleotide state of Ras becomes more dependent on relative nucleotide affinity and concentration. This gives GTP an advantage over GDP and increases the proportion of active GTP-bound Ras. Here we report the development of small molecules that irreversibly bind to a common oncogenic mutant, K-Ras(G12C). These compounds rely on the mutant cysteine for binding and therefore do not affect the wild-type protein. Crystallographic studies reveal the formation of a new pocket that is not apparent in previous structures of Ras, beneath the effector binding switch-II region. Binding of these inhibitors to K-Ras(G12C) disrupts both switch-I and switch-II, subverting the native nucleotide preference to favour GDP over GTP and impairing binding to Raf. Our data provide structure-based validation of a new allosteric regulatory site on Ras that is targetable in a mutant-specific manner.

PubMed: 24256730
DOI: 10.1038/nature12796

Experimental method

X-RAY DIFFRACTION (2.09 Å)