PDBsum entry 3fcs

Cell adhesion/blood clotting

PDB id: 3fcs

Contents

Protein chains

914 a.a. *

680 a.a. *

603 a.a. *

Ligands

NAG-NAG ×7

NAG-NAG-MAN-MAN

NAG-NAG-MAN

NAG-NAG-MAN-MAN-MAN

NAG ×5

IMD ×6

Metals

_CA ×14

_MG ×2

Waters ×678

* Residue conservation analysis

PDB id:

3fcs

Name:

Cell adhesion/blood clotting

Title:

Structure of complete ectodomain of integrin aiibb3

Structure:

Integrin, alpha 2b. Chain: a, c. Fragment: unp residues 32-989, ectodomain. Engineered: yes. Integrin beta-3. Chain: b, d. Fragment: unp residues 27-716, extracellular domain. Synonym: platelet membrane glycoprotein iiia, gpiiia. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: itga2b. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Gene: itgb3, gp3a. Expression_system_taxid: 10029

Resolution:

2.55Å R-factor: 0.233 R-free: 0.268

Authors:

J.Zhu,B.-H.Luo,T.Xiao,C.Zhang,N.Nishida,T.A.Springer

Key ref:

J.Zhu et al. (2008). Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces. Mol Cell, 32, 849-861. PubMed id: 19111664 DOI: 10.1016/j.molcel.2008.11.018

Date:

22-Nov-08 Release date: 20-Jan-09

Protein chains

P08514  (ITA2B_HUMAN) -  Integrin alpha-IIb from Homo sapiens

Seq: 1039 a.a.

Struc: 914 a.a.*

Protein chain

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

Seq: 788 a.a.

Struc: 680 a.a.*

Protein chain

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

Seq: 788 a.a.

Struc: 603 a.a.

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1016/j.molcel.2008.11.018

Mol Cell 32:849-861 (2008)

PubMed id: 19111664

Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces.

J.Zhu, B.H.Luo, T.Xiao, C.Zhang, N.Nishida, T.A.Springer.

ABSTRACT

The complete ectodomain of integrin alpha(IIb)beta(3) reveals a bent, closed, low-affinity conformation, the beta knee, and a mechanism for linking cytoskeleton attachment to high affinity for ligand. Ca and Mg ions in the recognition site, including the synergistic metal ion binding site (SyMBS), are loaded prior to ligand binding. Electrophilicity of the ligand-binding Mg ion is increased in the open conformation. The beta(3) knee passes between the beta(3)-PSI and alpha(IIb)-knob to bury the lower beta leg in a cleft, from which it is released for extension. Different integrin molecules in crystals and EM reveal breathing that appears on pathway to extension. Tensile force applied to the extended ligand-receptor complex stabilizes the closed, low-affinity conformation. By contrast, an additional lateral force applied to the beta subunit to mimic attachment to moving actin filaments stabilizes the open, high-affinity conformation. This mechanism propagates allostery over long distances and couples cytoskeleton attachment of integrins to their high-affinity state.

Selected figure(s)

Figure 3.
Figure 3. Metal Ion Rearrangements in β I Domain Activation
(A) Superposition of headpieces from our unliganded-closed structure and liganded-open α[IIb]β[3] (Springer et al., 2008). The β I and hybrid domains are yellow (open) and magenta (closed), while PSI and I-EGF1 domains are red and green, respectively. The α headpieces are cyan (open) and gray (closed).
(B) Enlarged view of β I domains with major differences in yellow (open) and magenta (closed).
(C and D) β I domain metal coordination sites in unliganded-closed α[IIb]β[3] (C) and liganded-open α[IIb]β[3] (D). Ca (gold) and Mg (green) ions are large spheres; waters (red or pink) are smaller spheres. N atoms are blue and O atoms are red or pink. Metal coordination and hydrogen bonds are dashed. The loop bearing M335 moves far away in (D).
(E) Superposition at the β I MIDAS.
(F) Superposition at the α I MIDAS of unliganded-closed (PDB code 1LFA) and liganded-open α[L] (PDB code 1T0P) in the same orientation as the β I MIDAS in (D). In (C)–(F), carbons for unliganded-closed and liganded-open integrins and for ligands are wheat, gray, and cyan, respectively.
(G and H) Electrostatic potential surfaces at the unliganded (G) and liganded (H) binding sites.

Figure 5.
Figure 5. The Integrin Cycle
(A) In the bent conformation, integrins have low affinity for ligand.
(B) At sites where actin filaments are formed, the integrin β subunit cytoplasmic domain binds through talin or kindlins. Lateral translocation on the cell surface and buffeting cause integrin extension. Both open and closed headpiece conformations are putatively present.
(C) Binding to an immobilized extracellular ligand greatly increases the lateral force and markedly favors the high-affinity, open headpiece conformation.
(D) Disassembly of the actin cytoskeleton removes the lateral force. Tensile force between the ligand and the integrin cytoplasmic domains favors the closed headpiece conformation and ligand dissociation.
(E) Ligand dissociates, further favoring the closed headpiece conformation.
(F) In the absence of ligand and tensile force, the bent conformation is favored, completing the cycle, and the integrin returns to the same state as shown in (A).

The above figures are reprinted from an Open Access publication published by Cell Press: Mol Cell (2008, 32, 849-861) copyright 2008.

Figures were selected by an automated process.