8HYI

Crystal structure of human P-cadherin MEC12 (X dimer) in complex with 2-(2-methyl-5-phenyl-1H-indole-3-yl)ethan-1-amine

Summary for 8HYI

• Entry DOI: 10.2210/pdb8hyi/pdb
• Descriptor: Cadherin-3, 2-(2-methyl-5-phenyl-1H-indole-3-yl)ethan-1-amine, DIMETHYL SULFOXIDE, ... (4 entities in total)
• Functional Keywords: inhibitor, cell adhesion
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 47741.43

Authors

Senoo, A.,Ito, S.,Ueno, G.,Nagatoishi, S.,Tsumoto, K. (deposition date: 2023-01-06, release date: 2023-08-30, Last modification date: 2023-10-11)

Primary citation

Senoo, A.,Nagatoishi, S.,Kuroda, D.,Ito, S.,Ueno, G.,Caaveiro, J.M.M.,Tsumoto, K.
Modulation of a conformational ensemble by a small molecule that inhibits key protein-protein interactions involved in cell adhesion.
Protein Sci., 32:e4744-e4744, 2023

PubMed Abstract: 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.

PubMed: 37531208
DOI: 10.1002/pro.4744

Experimental method

X-RAY DIFFRACTION (2.85 Å)