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Optical Control of the GTP Affinity of K‐Ras(G12C) by a Photoswitchable Inhibitor
Author(s) -
Ge Zhihua,
Yang Zhuojin,
Liang Jingshi,
Dong Duoling,
Zhu Mingyan
Publication year - 2019
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201900342
Subject(s) - gtp' , chemistry , biochemistry , enzyme
Photocontrol of protein activity is an emerging field in biomedicine. For optical control of a mutant small GTPase K‐Ras(G12C), we developed small‐molecule inhibitors with photoswitchable efficacy, where one configuration binds the target protein and exert different pharmacological effects upon light irradiation. The compound design was based on the structure feature of a previously identified allosteric pocket of K‐Ras(G12C) and the chemical structure of covalent inhibitors, and resulted in the synthesis and characterization of two representative azobenzene‐containing compounds. Nucleotide exchange assays demonstrated the different efficacy to control the GTP affinity by photoswitching of one potent compound PS‐C2, which would be a useful tool to probe the conformation of mutational K‐Ras. Our study demonstrated the feasibility of designing photoswitchable modulators from allosteric covalent inhibitor of small GTPases.