4MMZ

Integrin AlphaVBeta3 ectodomain bound to an antagonistic tenth domain of Fibronectin

Summary for 4MMZ

• Entry DOI: 10.2210/pdb4mmz/pdb
• Related: 1JV2 1L5G 3IJE 4G1E 4G1M 4MMX 4MMY
• Descriptor: Integrin alpha-V, GLYCEROL, Integrin beta-3, ... (11 entities in total)
• Functional Keywords: integrin, a domain, hybrid domain, psi, egf repeats, beta tail, calf, thigh, beta propeller, rgd motif, fibronectin, vitronectin, cell adhesion
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 198878.71

Authors

van Agthoven, J.,Xiong, J.,Arnaout, M.A. (deposition date: 2013-09-09, release date: 2014-03-26, Last modification date: 2024-11-20)

Primary citation

Van Agthoven, J.F.,Xiong, J.P.,Alonso, J.L.,Rui, X.,Adair, B.D.,Goodman, S.L.,Arnaout, M.A.
Structural basis for pure antagonism of integrin alpha V beta 3 by a high-affinity form of fibronectin.
Nat.Struct.Mol.Biol., 21:383-388, 2014

PubMed 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.

PubMed: 24658351
DOI: 10.1038/nsmb.2797

Experimental method

X-RAY DIFFRACTION (3.1 Å)