8gcd

Full length Integrin AlphaIIbBeta3 in inactive state

spinqualitylabelsall models 8gcd, resolution 2.97Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8gcd is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.97Å Ligands: BMA, CA, MAN, MG, NAG 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 Integrin alphaIIbbeta3 is the key receptor regulating platelet retraction and accumulation and a proven drug-target for antithrombotic therapies. Here we resolve the cryo-EM structures of the full-length alphaIIbbeta3, which covers three distinct states along the activation pathway. Firstly, we obtain the alphaIIbbeta3 structure at 3 A resolution in the inactive state, revealing the overall topology of the heterodimer with the transmembrane (TM) helices and the ligand-binding domain tucked in a specific angle proximity to the TM region. After the addition of a Mn(2+) agonist, we resolve two coexisting structures representing two new states between inactive and active state. Our structures show conformational changes of the alphaIIbbeta3 activating trajectory and a unique twisting of the integrin legs, which is required for platelets accumulation. Our structure provides direct structural evidence for how the lower legs are involved in full-length integrin activation mechanisms and offers a new strategy to target the alphaIIbbeta3 lower leg. Full-length alphaIIbbeta3 cryo-EM structure reveals intact integrin initiate-activation intrinsic architecture.,Huo T, Wu H, Moussa Z, Sen M, Dalton V, Wang Z Structure. 2024 Jul 11;32(7):899-906.e3. doi: 10.1016/j.str.2024.03.006. Epub , 2024 Apr 4. PMID:38579706 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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