1TYE

Structural basis for allostery in integrins and binding of ligand-mimetic therapeutics to the platelet receptor for fibrinogen

Summary for 1TYE

• Entry DOI: 10.2210/pdb1tye/pdb
• Related: 1TXV 1TY3 1TY5 1TY6 1TY7
• Descriptor: Integrin alpha-IIb, Integrin beta-3, beta-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: crystal structure; platelet integrin alphaiibbeta3; fibrinogen binding; allostery; therapeutic antagonism, cell adhesion
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 298452.84

Authors

Xiao, T.,Takagi, J.,Coller, B.S.,Wang, J.-H.,Springer, T.A. (deposition date: 2004-07-07, release date: 2004-10-12, Last modification date: 2024-10-09)

Primary citation

Xiao, T.,Takagi, J.,Coller, B.S.,Wang, J.-H.,Springer, T.A.
Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics
Nature, 432:59-67, 2004

PubMed Abstract: Integrins are important adhesion receptors in all Metazoa that transmit conformational change bidirectionally across the membrane. Integrin alpha and beta 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 alpha(IIb)beta3. Allostery in the beta3 I domain alters three metal binding sites, associated loops and alpha1- and alpha7-helices. Piston-like displacement of the alpha7-helix causes a 62 degrees reorientation between the beta3 I and hybrid domains. Transmission through the rigidly connected plexin/semaphorin/integrin (PSI) domain in the upper beta3 leg causes a 70 A separation between the knees of the alpha and beta 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.

PubMed: 15378069
DOI: 10.1038/nature02976

Experimental method

X-RAY DIFFRACTION (2.9 Å)