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Publication Abstract from PubMed

Small molecules that regulate protein-protein interactions can be valuable drugs; however, the development of such small molecules is challenging as the molecule must interfere with an interaction that often involves a large surface area. Herein, we propose that modulating the conformational ensemble of the proteins participating in a given interaction, rather than blocking the interaction by directly binding to the interface, is a relevant strategy for interfering with a protein-protein interaction. In this study, we applied this concept to P-cadherin, a cell surface protein forming homodimers that are essential for cell-cell adhesion in various biological contexts. We first determined the crystal structure of P-cadherin with a small molecule inhibitor whose inhibitory mechanism was unknown. Molecular dynamics simulations suggest that the inhibition of cell adhesion by this small molecule results from modulation of the conformational ensemble of P-cadherin. Our study demonstrates the potential of small molecules altering the conformation ensemble of a protein as inhibitors of biological relevant protein-protein interactions.

Modulation of a conformational ensemble by a small molecule that inhibits key protein-protein interactions involved in cell adhesion.,Senoo A, Nagatoishi S, Kuroda D, Ito S, Ueno G, Caaveiro JMM, Tsumoto K Protein Sci. 2023 Sep;32(9):e4744. doi: 10.1002/pro.4744. PMID:37531208^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.