THE CRYSTAL-STRUCTURE OF AN N-TERMINAL 2-DOMAIN FRAGMENT OF VASCULAR CELL-ADHESION MOLECULE-1 (VCAM-1) - A CYCLIC PEPTIDE-BASED ON THE DOMAIN-1 C-D LOOP CAN INHIBIT VCAM-1-ALPHA-4 INTEGRIN INTERACTION

Vascular cell adhesion molecule 1 (VCAM-1) represents a structurally and functionally distinct class of immunoglobulin superfamily molecules that bind leukocyte integrins and are involved in inflammatory and immune functions, X-ray crystallography defines the three-dimensional structure of the N-terminal two-domain fragment that participates in ligand binding, Residues in domain 1 important for ligand binding reside in the C-D loop, which projects markedly from one face of the molecule near the contact between domains 1 and 2, A cyclic peptide that mimics this loop inhibits binding of alpha 4 beta 1 integrin-bearing cells to VCAM-1. These data demonstrate how crystallographic structural information can be used to design a small molecule inhibitor of biological function.