Regulation of cadherin dimerization by chemical fragments as a trigger to inhibit cell adhesion.

Akinobu Senoo, Sho Ito, Satoru Nagatoishi, Yutaro Saito, Go Ueno, Daisuke Kuroda, Kouhei Yoshida, Takumi Tashima, Shota Kudo, Shinsuke Sando, Kouhei Tsumoto

Communications biology 2021 Sep 07

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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. © 2021. The Author(s).

Citation

Akinobu Senoo, Sho Ito, Satoru Nagatoishi, Yutaro Saito, Go Ueno, Daisuke Kuroda, Kouhei Yoshida, Takumi Tashima, Shota Kudo, Shinsuke Sando, Kouhei Tsumoto. Regulation of cadherin dimerization by chemical fragments as a trigger to inhibit cell adhesion. Communications biology. 2021 Sep 07;4(1):1041