Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics

Tsan Xiao, Junichi Takagi, Barry S. Coller, Jia-Huai Wang and Timothy A. Springer ()
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Tsan Xiao: Harvard Medical School
Junichi Takagi: Harvard Medical School
Barry S. Coller: The Rockefeller University
Jia-Huai Wang: Biological Chemistry and Molecular Pharmacology, Harvard Medical School
Timothy A. Springer: Harvard Medical School

Nature, 2004, vol. 432, issue 7013, 59-67

Abstract: Abstract Integrins are important adhesion receptors in all Metazoa that transmit conformational change bidirectionally across the membrane. Integrin α and β 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 αIIbβ3. Allostery in the β3 I domain alters three metal binding sites, associated loops and α1- and α7-helices. Piston-like displacement of the α7-helix causes a 62° reorientation between the β3 I and hybrid domains. Transmission through the rigidly connected plexin/semaphorin/integrin (PSI) domain in the upper β3 leg causes a 70 Å separation between the knees of the α and β 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.

Date: 2004
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DOI: 10.1038/nature02976

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