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Science 296 (5565): 151-155

Copyright © 2002 by the American Association for the Advancement of Science

Crystal Structure of the Extracellular Segment of Integrin alpha Vbeta 3 in Complex with an Arg-Gly-Asp Ligand

Jian-Ping Xiong,1 Thilo Stehle,12* Rongguang Zhang,3* Andrzej Joachimiak,3 Matthias Frech,4 Simon L. Goodman,5 M. Amin Arnaout1dagger

The structural basis for the divalent cation-dependent binding of heterodimeric alpha beta integrins to their ligands, which contain the prototypical Arg-Gly-Asp sequence, is unknown. Interaction with ligands triggers tertiary and quaternary structural rearrangements in integrins that are needed for cell signaling. Here we report the crystal structure of the extracellular segment of integrin alpha Vbeta 3 in complex with a cyclic peptide presenting the Arg-Gly-Asp sequence. The ligand binds at the major interface between the alpha V and beta 3 subunits and makes extensive contacts with both. Both tertiary and quaternary changes are observed in the presence of ligand. The tertiary rearrangements take place in beta A, the ligand-binding domain of beta 3; in the complex, beta A acquires two cations, one of which contacts the ligand Asp directly and the other stabilizes the ligand-binding surface. Ligand binding induces small changes in the orientation of alpha V relative to beta 3.

1 Renal Unit, Leukocyte Biology and Inflammation Program, Structural Biology Program, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02129, USA.
2 Laboratory of Developmental Immunology, Massachusetts General Hospital, and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
3 Argonne National Laboratory, Biosciences Division, Structural Biology Center, IL 60439, USA.
4 Department of Target Research,
5 Biomedical Research, Oncology, Merck KGaA, Darmstadt 64271, Germany.
*   These two authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: arnaout{at}receptor.mgh.harvard.edu



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J. Cell Biol. 182, 791-800
   Abstract »    Full Text »    PDF »
The Croonian lecture 2006 Structure of the living cell.
I. D Campbell (2008)
Phil Trans R Soc B 363, 2379-2391
   Abstract »    Full Text »    PDF »
Structural Basis for the Interaction of isoDGR with the RGD-binding Site of {alpha}v{beta}3 Integrin.
A. Spitaleri, S. Mari, F. Curnis, C. Traversari, R. Longhi, C. Bordignon, A. Corti, G.-P. Rizzardi, and G. Musco (2008)
J. Biol. Chem. 283, 19757-19768
   Abstract »    Full Text »    PDF »
Multimodality Molecular Imaging of Tumor Angiogenesis.
W. Cai and X. Chen (2008)
J. Nucl. Med. 49, 113S-128S
   Abstract »    Full Text »    PDF »
Advances in Anatomic, Functional, and Molecular Imaging of Angiogenesis.
A. R. Hsu and X. Chen (2008)
J. Nucl. Med. 49, 511-514
   Abstract »    Full Text »    PDF »
Cell Adhesion Mechanisms in Platelets.
D. Varga-Szabo, I. Pleines, and B. Nieswandt (2008)
Arterioscler Thromb Vasc Biol 28, 403-412
   Abstract »    Full Text »    PDF »
Phase I Clinical Trial of Cilengitide in Children With Refractory Brain Tumors: Pediatric Brain Tumor Consortium Study PBTC-012.
T. J. MacDonald, C. F. Stewart, M. Kocak, S. Goldman, R. G. Ellenbogen, P. Phillips, D. Lafond, T. Y. Poussaint, M. W. Kieran, J. M. Boyett, et al. (2008)
J. Clin. Oncol. 26, 919-924
   Abstract »    Full Text »    PDF »
Role of the {beta}-Subunit Arginine/Lysine Finger in Integrin Heterodimer Formation and Function.
V. Gupta, J. L. Alonso, T. Sugimori, M. Issafi, J.-P. Xiong, and M. A. Arnaout (2008)
J. Immunol. 180, 1713-1718
   Abstract »    Full Text »    PDF »
Fine specificity of drug-dependent antibodies reactive with a restricted domain of platelet GPIIIA.
J. A. Peterson, T. N. Nelson, A. J. Kanack, and R. H. Aster (2008)
Blood 111, 1234-1239
   Abstract »    Full Text »    PDF »
Application of high-throughput screening to identify a novel {alpha}IIb-specific small- molecule inhibitor of {alpha}IIb{beta}3-mediated platelet interaction with fibrinogen.
R. Blue, M. Murcia, C. Karan, M. Jirouskova, and B. S. Coller (2008)
Blood 111, 1248-1256
   Abstract »    Full Text »    PDF »
The Role of the Fibronectin IGD Motif in Stimulating Fibroblast Migration.
C. J. Millard, I. R. Ellis, A. R. Pickford, A. M. Schor, S. L. Schor, and I. D. Campbell (2007)
J. Biol. Chem. 282, 35530-35535
   Abstract »    Full Text »    PDF »
Dual-Function Probe for PET and Near-Infrared Fluorescence Imaging of Tumor Vasculature.
W. Cai, K. Chen, Z.-B. Li, S. S. Gambhir, and X. Chen (2007)
J. Nucl. Med. 48, 1862-1870
   Abstract »    Full Text »    PDF »
{alpha}vbeta5 Integrin Sustains Growth of Human Pre-B Cells through an RGD-independent Interaction with a Basic Domain of the CD23 Protein.
G. Borland, A. L. Edkins, M. Acharya, J. Matheson, L. J. White, J. M. Allen, J.-Y. Bonnefoy, B. W. Ozanne, and W. Cushley (2007)
J. Biol. Chem. 282, 27315-27326
   Abstract »    Full Text »    PDF »

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