4MMY

Integrin AlphaVBeta3 ectodomain bound to the tenth domain of Fibronectin with the IAKGDWND motif

4MMY の概要

• エントリーDOI: 10.2210/pdb4mmy/pdb
• 関連するPDBエントリー: 1JV2 1L5G 3IJE 4G1E 4G1M 4MMX 4MMZ
• 分子名称: Integrin alpha-V, Integrin beta-3, Fibronectin, ... (10 entities in total)
• 機能のキーワード: integrin, a domain, hybrid domain, psi, egf repeats, beta ta thigh, beta propeller, rgd motif, fibronectin, vitronectin, cell adhesion
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 200063.80

構造登録者

van Agthoven, J.,Xiong, J.,Arnaout, M.A. (登録日: 2013-09-09, 公開日: 2014-03-26, 最終更新日: 2024-11-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (3.183 Å)