1. The CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA
2. Laboratory of Blood and Vascular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA
3. Dana-Farber Cancer Institute, Departments of Pediatrics, Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 44 Binney Street, Boston, Massachusetts 02115, USA
4. Present address: Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan

Correspondence to: Timothy A. Springer¹ Email: springer@cbr.med.harvard.edu
Atomic coordinates and structural factors have been deposited with the Protein Data Bank with the accession codes 1TY3 (form A + cacodylate 1); 1TXV (form A + cacodylate 2); 1TY5 (form A + tirofiban); 1TY6 (form A + eptifibatide); 1TY7 (form A + L-739758); 1TYE (form B + cacodylate). Sequences of the 10E5 Fab have been deposited with GenBank.

Abstract

Integrins are important adhesion receptors in all Metazoa that transmit conformational change bidirectionally across the membrane. Integrin and subunits form a head and two long legs in the ectodomain and span the membrane. Here, we define with crystal structures the atomic basis for allosteric regulation of the conformation and affinity for ligand of the integrin ectodomain, and how fibrinogen-mimetic therapeutics bind to platelet integrin _IIb3. Allostery in the ₃ I domain alters three metal binding sites, associated loops and 1- and 7-helices. Piston-like displacement of the 7-helix causes a 62° reorientation between the ₃ I and hybrid domains. Transmission through the rigidly connected plexin/semaphorin/integrin (PSI) domain in the upper ₃ leg causes a 70 Å separation between the knees of the and legs. Allostery in the head thus disrupts interaction between the legs in a previously described low-affinity bent integrin conformation, and leg extension positions the high-affinity head far above the cell surface.

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