3hxo
From Proteopedia
Crystal Structure of Von Willebrand Factor (VWF) A1 Domain in Complex with DNA Aptamer ARC1172, an Inhibitor of VWF-Platelet Binding
Structural highlights
Disease[VWF_HUMAN] Defects in VWF are the cause of von Willebrand disease type 1 (VWD1) [MIM:193400]. A common hemorrhagic disorder due to defects in von Willebrand factor protein and resulting in impaired platelet aggregation. Von Willebrand disease type 1 is characterized by partial quantitative deficiency of circulating von Willebrand factor, that is otherwise structurally and functionally normal. Clinical manifestations are mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery or trauma.[1] [2] Defects in VWF are the cause of von Willebrand disease type 2 (VWD2) [MIM:613554]. A hemorrhagic disorder due to defects in von Willebrand factor protein and resulting in impaired platelet aggregation. Von Willebrand disease type 2 is characterized by qualitative deficiency and functional anomalies of von Willebrand factor. It is divided in different subtypes including 2A, 2B, 2M and 2N (Normandy variant). The mutant VWF protein in types 2A, 2B and 2M are defective in their platelet-dependent function, whereas the mutant protein in type 2N is defective in its ability to bind factor VIII. Clinical manifestations are mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery or trauma. Defects in VWF are the cause of von Willebrand disease type 3 (VWD3) [MIM:277480]. A severe hemorrhagic disorder due to a total or near total absence of von Willebrand factor in the plasma and cellular compartments, also leading to a profound deficiency of plasmatic factor VIII. Bleeding usually starts in infancy and can include epistaxis, recurrent mucocutaneous bleeding, excessive bleeding after minor trauma, and hemarthroses. Function[VWF_HUMAN] Important in the maintenance of hemostasis, it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V. Also acts as a chaperone for coagulation factor VIII, delivering it to the site of injury, stabilizing its heterodimeric structure and protecting it from premature clearance from plasma. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedARC1172 is a 41-mer DNA aptamer selected to bind the A1 domain of von Willebrand factor (VWF). A derivative of ARC1172 with modifications to increase intravascular survival inhibits carotid artery thrombosis in a Cynomolgus macaque model and inhibits VWF-dependent platelet aggregation in humans, suggesting that such aptamers may be useful to prevent or treat thrombosis. In the crystal structure of a VWF A1-ARC1172 complex, the aptamer adopts a three-stem structure of mainly B-form DNA with three noncanonical base pairs and 9 unpaired residues, 6 of which are stabilized by base-base or base-deoxyribose stacking interactions. The aptamer-protein interface is characterized by cation-pi interactions involving Arg, Lys, and Gln residues, often stabilized by H-bonds with adjacent bases. The ARC1172 binding site on the A1 domain overlaps with that of botrocetin and clashes with glycoprotein Ibalpha binding at an adjacent site, which accounts for the antithrombotic activity of ARC1172 and related aptamers. A structural explanation for the antithrombotic activity of ARC1172, a DNA aptamer that binds von Willebrand factor domain A1.,Huang RH, Fremont DH, Diener JL, Schaub RG, Sadler JE Structure. 2009 Nov 11;17(11):1476-84. PMID:19913482[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Diener, J L | Fremont, D H | Huang, R H | Sadler, J E | Schaub, R G | Aptamer | Arc1772 | Arc1779 | Blood clotting-blood clotting regulator complex | Blood coagulation | Cell adhesion | Cleavage on pair of basic residue | Disease mutation | Disulfide bond | Extracellular matrix | Glycoprotein | Hemostasis | Isopeptide bond | Platelet glycoprotein ib | Secreted | Von willebrand disease | Vwf
