TY - JOUR
T1 - A Structural Explanation for the Antithrombotic Activity of ARC1172, a DNA Aptamer that Binds von Willebrand Factor Domain A1
AU - Huang, Ren Huai
AU - Fremont, Daved H.
AU - Diener, John L.
AU - Schaub, Robert G.
AU - Sadler, J. Evan
N1 - Funding Information:
This study was supported by National Institute of Health Grants HL72917 (to J.E.S.), AI051426 and GM62414 (to D.H.F.) and by American Heart Association Midwest Affiliate Postdoctoral Fellowship Award 0825817G (to R.-H.H.).R.-H.H. and J.L.D. contributed to performing experiments; R.-H.H. and D.H.F. performed crystallization and structure determination; R.-H.H., R.G.S. and J.E.S. designed research; R.-H.H. and J.E.S. wrote the manuscript. All authors made comments on the manuscript.J.L.D. was employed and R.G.S is employed by Archemix Corp. J.E.S. is a consultant for Baxter Innovations and Ablynx, and is a member of clinical advisory boards for Baxter Innovations.
PY - 2009/11/11
Y1 - 2009/11/11
N2 - 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.
AB - 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.
KW - DNA
UR - http://www.scopus.com/inward/record.url?scp=70350705718&partnerID=8YFLogxK
U2 - 10.1016/j.str.2009.09.011
DO - 10.1016/j.str.2009.09.011
M3 - Article
C2 - 19913482
AN - SCOPUS:70350705718
SN - 0969-2126
VL - 17
SP - 1476
EP - 1484
JO - Structure
JF - Structure
IS - 11
ER -