4z7n

Integrin alphaIIbbeta3 in complex with AGDV peptideIntegrin alphaIIbbeta3 in complex with AGDV peptide

Structural highlights 4z7n is a 10 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.599Å Ligands: , , , , , , , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease ITA2B_HUMAN Defects in ITGA2B are a cause of Glanzmann thrombasthenia (GT) [MIM:273800; also known as thrombasthenia of Glanzmann and Naegeli. GT is the most common inherited disease of platelets. It is an autosomal recessive disorder characterized by mucocutaneous bleeding of mild-to-moderate severity and the inability of this integrin to recognize macromolecular or synthetic peptide ligands. GT has been classified clinically into types I and II. In type I, platelets show absence of the glycoprotein IIb/beta-3 complexes at their surface and lack fibrinogen and clot retraction capability. In type II, the platelets express the glycoprotein IIb/beta-3 complex at reduced levels (5-20% controls), have detectable amounts of fibrinogen, and have low or moderate clot retraction capability. The platelets of GT 'variants' have normal or near normal (60-100%) expression of dysfunctional receptors. Function ITA2B_HUMAN Integrin alpha-IIb/beta-3 is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. It recognizes the sequence R-G-D in a wide array of ligands. It recognizes the sequence H-H-L-G-G-G-A-K-Q-A-G-D-V in fibrinogen gamma chain. Following activation integrin alpha-IIb/beta-3 brings about platelet/platelet interaction through binding of soluble fibrinogen. This step leads to rapid platelet aggregation which physically plugs ruptured endothelial cell surface. Publication Abstract from PubMed The platelet integrin alphaIIbbeta3 binds to a KQAGDV motif at the fibrinogen gamma-chain C-terminus and to RGD motifs present in loops in many extracellular matrix proteins. These ligands bind in a groove between the integrin alpha and beta subunits; the basic Lys or Arg sidechain hydrogen bonds to the alphaIIb-subunit and the acidic Asp sidechain coordinates to a metal ion held by the beta3-subunit. Ligand binding induces headpiece opening, with conformational change in the beta-subunit. During this opening, RGD slides in the ligand-binding pocket towards alphaIIb, with movement of the betaI-domain beta1-alpha1 loop toward alphaIIb, enabling formation of direct, charged hydrogen bonds between the Arg sidechain and alphaIIb. Here we test whether ligand interactions with beta3 suffice for stable ligand binding and headpiece opening. We find that the AGDV tetrapeptide from KQAGDV binds to the alphaIIbbeta3 headpiece with affinity comparable to the RGDSP peptide from fibronectin. AGDV induced complete headpiece opening in solution as shown by increase in hydrodynamic radius. Soaking of AGDV into closed alphaIIbbeta3 headpiece crystals induced intermediate states similarly to RGDSP. AGDV has very little contact with the alpha subunit. Furthermore, as measured by epitope exposure, AGDV, like the fibrinogen gamma C-terminal peptide and RGD, caused integrin extension on the cell surface. Thus, pushing by the beta3 subunit on Asp is sufficient for headpiece opening and ligand sliding, and no pulling by the alphaIIb subunit on Arg is required. beta-subunit Binding is Sufficient for Ligands to open the Integrin alphaIIbbeta3 Headpiece.,Lin FY, Zhu J, Eng ET, Hudson NE, Springer TA J Biol Chem. 2015 Dec 2. pii: jbc.M115.705624. PMID:26631735 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Integrin 3D structures Monoclonal Antibodies 3D structures

spinqualitylabelsall models 4z7n, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image