期刊
COMMUNICATIONS BIOLOGY
卷 4, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s42003-021-02575-3
关键词
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资金
- JSPS [19H05766, 16H02420]
- Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from Japan Agency for Medical Research and Development (AMED) [JP19am0101094]
- BINDS from AMED [JP19am0101070, JP19am0101086]
- World-leading Innovative Graduate Study Program for Life Science and Technology, The University of Tokyo, as part of the WISE Program (Doctoral Program for World-leading Innovative & Smart Education), MEXT, Japan
- Grants-in-Aid for Scientific Research [16H02420, 19H05766] Funding Source: KAKEN
The study identified a chemical fragment specific to P-cadherin that inhibits P-cadherin-mediated cell adhesion. Despite being a fragment compound, it indirectly prevents the formation of hydrogen bonds necessary for X dimer formation by binding to a cavity of P-cadherin, thereby modulating the process of X dimerization.
Many cadherin family proteins are associated with diseases such as cancer. Since cell adhesion requires homodimerization of cadherin molecules, a small-molecule regulator of dimerization would have therapeutic potential. Herein, we describe identification of a P-cadherin-specific chemical fragment that inhibits P-cadherin-mediated cell adhesion. Although the identified molecule is a fragment compound, it binds to a cavity of P-cadherin that has not previously been targeted, indirectly prevents formation of hydrogen bonds necessary for formation of an intermediate called the X dimer and thus modulates the process of X dimerization. Our findings will impact on a strategy for regulation of protein-protein interactions and stepwise assembly of protein complexes using small molecules. Senoo et al. describe a chemical fragment that disrupts dimerization of P-cadherin. In doing so, this fragment inhibits cadherin-mediated cell-adhesion and aggregation.
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