A Structural Explanation for the Antithrombotic Activity of ARC1172, a DNA Aptamer that Binds von Willebrand Factor Domain A1

Ren Huai Huang, Daved H. Fremont, John L. Diener, Robert G. Schaub, J. Evan Sadler

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

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-π 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 Ibα binding at an adjacent site, which accounts for the antithrombotic activity of ARC1172 and related aptamers.

Original languageEnglish
Pages (from-to)1476-1484
Number of pages9
JournalStructure
Volume17
Issue number11
DOIs
StatePublished - Nov 11 2009

Keywords

  • DNA

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