期刊
ADVANCED SCIENCE
卷 7, 期 14, 页码 -出版社
WILEY
DOI: 10.1002/advs.202000098
关键词
anti-metastasis activities; crystal structures; inhibitors; novel pockets; rho family proteins
资金
- Ministry of Science and Technology of China [2015CB910304]
- National Natural Science Foundation of China [81625022, 91853205, 81821005, 21820102008, 31270830, 21572038]
- Chinese Academy of Science [XDA12020353]
- K. C. Wong Education Foundation
- National Science and Technology Major Project [2018ZX09711002]
- Science and Technology Commission of Shanghai Municipality [18431907100, 19XD1404700]
- Key Project of High-level University Construction of Guangzhou University of Chinese Medicine [XK2018019, YN2015MS03]
The Rho family GTPases are crucial drivers of tumor growth and metastasis. However, it is difficult to develop GTPases inhibitors due to a lack of well-characterized binding pockets for compounds. Here, through molecular dynamics simulation of the RhoA protein, a groove around cysteine 107 (Cys107) that is relatively well-conserved within the Rho family is discovered. Using a combined strategy, the novel inhibitor DC-Rhoin is discovered, which disrupts interaction of Rho proteins with guanine nucleotide exchange factors (GEFs) and guanine nucleotide dissociation inhibitors (GDIs). Crystallographic studies reveal that the covalent binding of DC-Rhoin to the Cys107 residue stabilizes and captures a novel allosteric pocket. Moreover, the derivative compound DC-Rhoin04 inhibits the migration and invasion of cancer cells, through targeting this allosteric pocket of RhoA. The study reveals a novel allosteric regulatory site within the Rho family, which can be exploited for anti-metastasis drug development, and also provides a novel strategy for inhibitor discovery toward undruggable protein targets.
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