PDBsum entry 4mmy

Cell adhesion

PDB id: 4mmy

Contents

Protein chains

924 a.a.

690 a.a.

Ligands

VAL-ILE-ALA-ARG-GLY-ASP-TRP-ASN

NAG-NAG-BMA-MAN ×2

NAG-NAG ×4

NAG-NAG-BMA-BMA-MAN-MAN

NAG-NAG-BMA ×2

NAG ×5

Metals

_MN ×8

Waters ×5

References listed in PDB file

Key reference

• Title: Structural basis for pure antagonism of integrin αVβ3 by a high-Affinity form of fibronectin.
• Authors: J.F.Van agthoven, J.P.Xiong, J.L.Alonso, X.Rui, B.D.Adair, S.L.Goodman, M.A.Arnaout.
• Ref.: Nat Struct Biol, 2014, 21, 383-388. [DOI no: 10.1038/nsmb.2797]
• PubMed id: 24658351

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.