3HXQ

Crystal Structure of Von Willebrand Factor (VWF) A1 Domain in Complex with DNA Aptamer ARC1172, an Inhibitor of VWF-Platelet Binding

Summary for 3HXQ

• Entry DOI: 10.2210/pdb3hxq/pdb
• Related: 3HXO
• Descriptor: von Willebrand Factor, Aptamer ARC1172 (3 entities in total)
• Functional Keywords: arc1779, vwf, platelet glycoprotein ib, aptamer, arc1772, blood coagulation, cell adhesion, cleavage on pair of basic residues, disease mutation, disulfide bond, extracellular matrix, glycoprotein, hemostasis, isopeptide bond, secreted, von willebrand disease, blood clotting-blood clotting regulator complex, blood clotting/blood clotting regulator
• Biological source: Homo sapiens; More
• Cellular location: Secreted : P04275
• Total number of polymer chains: 2
• Total formula weight: 36773.82

Authors

Huang, R.H.,Sadler, J.E.,Fremont, D.H.,Diener, J.L.,Schaub, R.G. (deposition date: 2009-06-21, release date: 2009-11-17, Last modification date: 2024-11-27)

Primary citation

Huang, R.H.,Fremont, D.H.,Diener, J.L.,Schaub, R.G.,Sadler, J.E.
A structural explanation for the antithrombotic activity of ARC1172, a DNA aptamer that binds von Willebrand factor domain A1.
Structure, 17:1476-1484, 2009

PubMed Abstract: ARC1172 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.

PubMed: 19913482
DOI: 10.1016/j.str.2009.09.011

Experimental method

X-RAY DIFFRACTION (2.694 Å)