title: Structural basis for pure antagonism of integrin αVβ3 by a high-affinity form of fibronectin.
abstract: 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 αVβ3 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 π-π interaction between Trp1496 in the RGD-containing loop of hFN10 and Tyr122 of the β3 subunit that blocked conformational changes triggered by wtFN10 and trapped hFN10-bound αVβ3 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.
authors.affiliation: 1] Structural Biology Program, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts, USA. [2].
authors.forename: Johannes F
authors.initials: JF
authors.lastname: Van Agthoven
authors.affiliation: 1] Structural Biology Program, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts, USA. [2].
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Xiong
authors.affiliation: Leukocyte Biology and Inflammation Program, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Alonso
authors.affiliation: Leukocyte Biology and Inflammation Program, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors.forename: Xianliang
authors.initials: X
authors.lastname: Rui
authors.affiliation: Structural Biology Program, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Adair
authors.affiliation: Global Research and Early Development, Translational Innovation Platform, Oncology, Merck KGaA, Darmstadt, Germany.
authors.forename: Simon L
authors.initials: SL
authors.lastname: Goodman
authors.affiliation: 1] Structural Biology Program, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts, USA. [2] Leukocyte Biology and Inflammation Program, Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors.forename: M Amin
authors.initials: MA
authors.lastname: Arnaout
mesh_terms: D001665:Binding Sites; D002448:Cell Adhesion; D018360:Crystallography, X-Ray; D005353:Fibronectins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D008958:Models, Molecular; D017434:Protein Structure, Tertiary
chemical_list: D005353:Fibronectins; D039302:Integrin alphaVbeta3