期刊
CELL CHEMICAL BIOLOGY
卷 23, 期 9, 页码 1135-1146出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2016.07.015
关键词
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资金
- AIRC-Italy [IG10740, IG14811]
- Swiss National Science Foundation [31003A_156713]
- Wellcome Trust
- MRC
- CAIP
- BBSRC [BB/I013865/1, BB/H019383/1, BB/H024697/1] Funding Source: UKRI
- MRC [MC_PC_13057] Funding Source: UKRI
- Swiss National Science Foundation (SNF) [31003A_156713] Funding Source: Swiss National Science Foundation (SNF)
- Biotechnology and Biological Sciences Research Council [BB/H019383/1, BB/H024697/1, BB/I013865/1, BBS/B/10714] Funding Source: researchfish
- Medical Research Council [MC_PC_13057] Funding Source: researchfish
Uncontrolled activation ofRhosignaling by RhoGEFs, in particular AKAP13 (Lbc) and its close homologs, is implicated in a number of human tumors with poor prognosis and resistance to therapy. Structure predictions and alanine scanning mutagenesis of Lbc identified a circumscribed hot region for RhoA recognition and activation. Virtual screening targeting that region led to the discovery of an inhibitor of Lbc-RhoA interaction inside cells. By interacting with the DH domain, the compound inhibits the catalytic activity of Lbc, halts cellular responses to activation of oncogenic Lbc pathways, and reverses a number of prostate cancer cell phenotypes such as proliferation, migration, and invasiveness. This study provides insights into the structural determinants of Lbc-RhoA recognition. This is a successful example of structure-based discovery of a small protein-protein interaction inhibitor able to halt oncogenic Rho signaling in cancer cells with therapeutic implications.
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