5V6S

Crystal structure of small molecule acrylamide 1 covalently bound to K-Ras G12C

Summary for 5V6S

• Entry DOI: 10.2210/pdb5v6s/pdb
• Related: 5v6v
• Descriptor: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: k-ras g12c, covalent inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 20273.20

Authors

McGregor, L.M.,Jenkins, M.,Kerwin, C.,Burke, J.E.,Shokat, K.M. (deposition date: 2017-03-17, release date: 2017-06-28, Last modification date: 2024-11-20)

Primary citation

McGregor, L.M.,Jenkins, M.L.,Kerwin, C.,Burke, J.E.,Shokat, K.M.
Expanding the Scope of Electrophiles Capable of Targeting K-Ras Oncogenes.
Biochemistry, 56:3178-3183, 2017

PubMed Abstract: There is growing interest in reversible and irreversible covalent inhibitors that target noncatalytic amino acids in target proteins. With a goal of targeting oncogenic K-Ras variants (e.g., G12D) by expanding the types of amino acids that can be targeted by covalent inhibitors, we survey a set of electrophiles for their ability to label carboxylates. We functionalized an optimized ligand for the K-Ras switch II pocket with a set of electrophiles previously reported to react with carboxylates and characterized the ability of these compounds to react with model nucleophiles and oncogenic K-Ras proteins. Here, we report that aziridines and stabilized diazo groups preferentially react with free carboxylates over thiols. Although we did not identify a warhead that potently labels K-Ras G12D, we were able to study the interactions of many electrophiles with K-Ras, as most of the electrophiles rapidly label K-Ras G12C. We characterized the resulting complexes by crystallography, hydrogen/deuterium exchange, and differential scanning fluorimetry. Our results both demonstrate the ability of a noncatalytic cysteine to react with a diverse set of electrophiles and emphasize the importance of proper spatial arrangements between a covalent inhibitor and its intended nucleophile. We hope that these results can expand the range of electrophiles and nucleophiles of use in covalent protein modulation.

PubMed: 28621541
DOI: 10.1021/acs.biochem.7b00271

Experimental method

X-RAY DIFFRACTION (1.7 Å)