The crystal structure of an N-terminal two-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.
Wang
J H
JH
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Pepinsky
R B
RB
Stehle
T
T
Liu
J H
JH
Karpusas
M
M
Browning
B
B
Osborn
L
L
D000595:Amino Acid Sequence; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000378:metabolism; D003196:Computer Graphics; D018360:Crystallography, X-Ray; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D019010:Vascular Cell Adhesion Molecule-1
D015815:Cell Adhesion Molecules; D039041:Integrin alpha4beta1; D016023:Integrins; D010456:Peptides, Cyclic; D019010:Vascular Cell Adhesion Molecule-1