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

PDB id:

4mmy

Name:

Cell adhesion

Title:

Integrin alphavbeta3 ectodomain bound to the tenth domain of fibronectin with the iakgdwnd motif

Structure:

Integrin alpha-v. Chain: a. Fragment: extracellular domain (unp residues 31-989). Synonym: vitronectin receptor subunit alpha, integrin alpha-v heavy chain, integrin alpha-v light chain. Engineered: yes. Integrin beta-3. Chain: b. Fragment: extracellular domain (unp residues 27-718).

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: itgav, msk8, vnra. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: itgb3, gp3a. Gene: fn1, fn. Expressed in: escherichia coli.

Resolution:

3.18Å R-factor: 0.213 R-free: 0.252

Authors:

J.Van Agthoven,J.Xiong,M.A.Arnaout

Key ref:

J.F.Van Agthoven et al. (2014). Structural basis for pure antagonism of integrin αVβ3 by a high-affinity form of fibronectin. Nat Struct Biol, 21, 383-388. PubMed id: 24658351 DOI: 10.1038/nsmb.2797

Date:

09-Sep-13 Release date: 26-Mar-14

Protein chain

P06756  (ITAV_HUMAN) -  Integrin alpha-V from Homo sapiens

Seq: 1048 a.a.

Struc: 924 a.a.

Protein chain

P05106  (ITB3_HUMAN) -  Integrin beta-3 from Homo sapiens

Seq: 788 a.a.

Struc: 690 a.a.

DOI no: 10.1038/nsmb.2797

Nat Struct Biol 21:383-388 (2014)

PubMed id: 24658351

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

J.F.Van Agthoven, J.P.Xiong, J.L.Alonso, X.Rui, B.D.Adair, S.L.Goodman, M.A.Arnaout.

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.