Crystal structure of human E-cadherin-EC1EC2 in complex with a peptidomimetic competitive inhibitor of cadherin homophilic interactions

Cadherins are transmembrane cell adhesion proteins whose aberrant expression often correlates with cancer development and proliferation [1]. Cadherins mediate cell-cell adhesion by means of a concerted mechanism whereby proteins protruding from opposing cells interact with each other at the cellular adherens junctions [2]. All classical cadherin family members share a high degree of homology and structural similarity. Classical cadherins comprise an elongated extracellular portion formed by five immunoglobulin-like extracellular cadherin domains (ECs) arranged in tandem, and an intracellular portion whose dynamic association with cytoplasmic molecules called catenins provides a physical link between the membrane-bound cadherins and the actin cytoskeleton. Owing to the intrinsic dynamic behavior of the cadherin extracellular portions, the rational design of small ligands targeting cadherin homophilic interactions has proved difficult and, until recently, no crystal structure existed of a complex between a cadherin molecule and an inhibitor. We report the first crystal structure of a cadherin extracellular fragment in complex with a small synthetic molecule, a peptidomimetic compound that modulates and partially inhibits adhesion of epithelial ovarian cancer cells [3]. The ligand binds across two interacting cadherin molecules in X-dimer configuration at the level of the di-proline motif of their adhesion arm. The phenyl ring of the peptidomimetic ligand fits into an hydrophobic cavity formed by the side chains of residues Ile4, Pro5, Ile7 and Val22 from both cadherin molecules. The hydrophobic cavity is symmetrical as it is formed by exactly the same group of residues from the two interacting proteins. These structural details allow the identification of a novel druggable cadherin interface and will therefore facilitate the structure-based design of new cell adhesion inhibitors against cadherin expressing solid tumors.