4WJK

Metal Ion and Ligand Binding of Integrin

Summary for 4WJK

• Entry DOI: 10.2210/pdb4wjk/pdb
• Related: 4WK0 4WK2 4WK4
• Descriptor: Integrin alpha-5, 2-acetamido-2-deoxy-beta-D-glucopyranose, Integrin beta-1, ... (11 entities in total)
• Functional Keywords: cell adhesion-immune system complex, cell adhesion/immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 103022.19

Authors

Xia, W.,Springer, T.A. (deposition date: 2014-09-30, release date: 2014-12-03, Last modification date: 2024-11-13)

Primary citation

Xia, W.,Springer, T.A.
Metal ion and ligand binding of integrin alpha 5 beta 1.
Proc.Natl.Acad.Sci.USA, 111:17863-17868, 2014

PubMed Abstract: Integrin α5β1 binds to an Arg-Gly-Asp (RGD) motif in its ligand fibronectin. We report high-resolution crystal structures of a four-domain α5β1 headpiece fragment, alone or with RGD peptides soaked into crystals, and RGD peptide affinity measurements. The headpiece crystallizes in a closed conformation essentially identical to that seen previously for α5β1 complexed with a Fab that allosterically inhibits ligand binding by stabilizing the closed conformation. Soaking experiments show that binding of cyclic RGD peptide with 20-fold higher affinity than a linear RGD peptide induces conformational change in the β1-subunit βI domain to a state that is intermediate between closed (low affinity) and open (high affinity). In contrast, binding of a linear RGD peptide induces no shape shifting. However, linear peptide binding induces shape shifting when Ca(2+) is depleted during soaking. Ca(2+) bound to the adjacent to metal ion-dependent adhesion site (ADMIDAS), at the locus of shape shifting, moves and decreases in occupancy, correlating with an increase in affinity for RGD measured when Ca(2+) is depleted. The results directly demonstrate that Ca(2+) binding to the ADMIDAS stabilizes integrins in the low-affinity, closed conformation. Comparisons in affinity between four-domain and six-domain headpiece constructs suggest that flexible integrin leg domains contribute to conformational equilibria. High-resolution views of the hybrid domain interface with the plexin-semaphorin-integrin (PSI) domain in different orientations show a ball-and-socket joint with a hybrid domain Arg side chain that rocks in a PSI domain socket lined with carbonyl oxygens.

PubMed: 25475857
DOI: 10.1073/pnas.1420645111

Experimental method

X-RAY DIFFRACTION (1.85 Å)