Fig: SPR-based fragment screening: a Illustration of the stepwise dimerization of P-cadherin to mediate cell adhesion and a schematic of the protein (EC12). b Schematic of fragment screening. The numbers in the parentheses show decreases in the number of fragment candidates. c Representative sensorgram from ABA assay. EC12, in monomer-S–S dimer equilibrium, was immobilized on Sensor Chip CM5. The decrease of response upon injection of solution B shows that the compound disrupted the dimer formed on the sensor chip. d Dose–response analysis of binding of Hit 1 to REC12 immobilized on Sensor Chip SA. The putative KD was calculated by the Scatchard method using the SPR responses in equilibrium. Note that the KDvalue is not reliable, since the binding response was not saturated even at the highest concentration of Hit 1. N = 3. e Chemical structure of Hit 1.
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, A., Ito, S., Nagatoishi, S. et al. Regulation of cadherin dimerization by chemical fragments as a trigger to inhibit cell adhesion. Commun Biol 4, 1041 (2021). https://doi.org/10.1038/s42003-021-02575-3