Structural basis for pure antagonism of integrin αVβ3 by a high-affinity form of fibronectin

被引:111
作者
Van Agthoven, Johannes F. [1 ]
Xiong, Jian-Ping [1 ]
Alonso, Jose Luis [2 ]
Rui, Xianliang [2 ]
Adair, Brian D. [1 ]
Goodman, Simon L. [3 ]
Arnaout, M. Amin [1 ,2 ]
机构
[1] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Struct Biol Program,Dept Med, Charlestown, MA USA
[2] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Leukocyte Biol & Inflammat Program,Dept Med, Charlestown, MA USA
[3] Merck KGaA, Translat Innovat Platform, Global Res & Early Dev, Oncol, Darmstadt, Germany
基金
美国国家卫生研究院;
关键词
CRYSTAL-STRUCTURE; EXTRACELLULAR SEGMENT; HUMAN-MELANOMA; BINDING-SITE; ALPHA-V-BETA-3; DOMAIN; ECTODOMAIN; THROMBOCYTOPENIA; IDENTIFICATION; SPECIFICITY;
D O I
10.1038/nsmb.2797
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Integrins are important therapeutic targets. However, current RGD-based anti-integrin drugs are also partial agonists, inducing conformational changes that trigger potentially fatal immune reactions and paradoxical cell adhesion. Here we describe the first crystal structure of alpha(V)beta(3) bound to a physiologic ligand, the tenth type III RGD domain of wild-type fibronectin (wtFN10), or to a high-affinity mutant (hFN10) shown here to act as a pure antagonist. Comparison of these structures revealed a central pi-pi interaction between Trp1496 in the RGD-containing loop of hFN10 and Tyr122 of the beta(3) subunit that blocked conformational changes triggered by wtFN10 and trapped hFN10-bound alpha(V)beta(3) in an inactive conformation. Removing the Trp1496 or Tyr122 side chains or reorienting Trp1496 away from Tyr122 converted hFN10 into a partial agonist. These findings offer new insights into the mechanism of integrin activation and a basis for the design of RGD-based pure antagonists.
引用
收藏
页码:383 / U174
页数:8
相关论文
共 45 条
[1]   Three-dimensional EM structure of the ectodomain of integrin αVβ3 in a complex with fibronectin [J].
Adair, BD ;
Xiong, JP ;
Maddock, C ;
Goodman, SL ;
Arnaout, MA ;
Yeager, M .
JOURNAL OF CELL BIOLOGY, 2005, 168 (07) :1109-1118
[2]   PHENIX: a comprehensive Python']Python-based system for macromolecular structure solution [J].
Adams, Paul D. ;
Afonine, Pavel V. ;
Bunkoczi, Gabor ;
Chen, Vincent B. ;
Davis, Ian W. ;
Echols, Nathaniel ;
Headd, Jeffrey J. ;
Hung, Li-Wei ;
Kapral, Gary J. ;
Grosse-Kunstleve, Ralf W. ;
McCoy, Airlie J. ;
Moriarty, Nigel W. ;
Oeffner, Robert ;
Read, Randy J. ;
Richardson, David C. ;
Richardson, Jane S. ;
Terwilliger, Thomas C. ;
Zwart, Peter H. .
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2010, 66 :213-221
[3]   The Integrin Antagonist Cilengitide Activates αVβ3, Disrupts VE-Cadherin Localization at Cell Junctions and Enhances Permeability in Endothelial Cells [J].
Alghisi, Gian Carlo ;
Ponsonnet, Lionel ;
Rueegg, Curzio .
PLOS ONE, 2009, 4 (02)
[4]   Structure and mechanics of integrin-based cell adhesion [J].
Arnaout, M. Amin ;
Goodman, Simon L. ;
Xiong, Jian-Ping .
CURRENT OPINION IN CELL BIOLOGY, 2007, 19 (05) :495-507
[5]   Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management [J].
Aster, R. H. ;
Curtis, B. R. ;
McFarland, J. G. ;
Bougie, D. W. .
JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2009, 7 (06) :911-918
[6]   A mechanistic model for paradoxical platelet activation by ligand-mimetic αIIbβ3 (GPIIb/IIIa) antagonists [J].
Bassler, Nicole ;
Loeffler, Christoph ;
Mangin, Pierre ;
Yuan, Yuping ;
Schwarz, Meike ;
Hagemeyer, Christoph E. ;
Eisenhardt, Steffen U. ;
Ahrens, Ingo ;
Bode, Christoph ;
Jackson, Shaun P. ;
Peter, Karlheinz .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2007, 27 (03) :E9-E15
[7]   iMOSFLM: a new graphical interface for diffraction-image processing with MOSFLM [J].
Battye, T. Geoff G. ;
Kontogiannis, Luke ;
Johnson, Owen ;
Powell, Harold R. ;
Leslie, Andrew G. W. .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 2011, 67 :271-281
[8]  
BOWDITCH RD, 1994, J BIOL CHEM, V269, P10856
[9]   Mutation of a conserved asparagine in the I-like domain promotes constitutively active integrins αLß2 and αIIbß3 [J].
Cheng, Ming ;
Foo, Shen-Yun ;
Shi, Min-Long ;
Tang, Ren-Hong ;
Kong, Le-Sheng ;
Law, S. K. Alex ;
Tan, Suet-Mien .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (25) :18225-18232