1. Structural Basis for Platelet Antiaggregation by Angiotensin II Type 1 Receptor Antagonist Losartan (DuP-753) via Glycoprotein VI
- Author
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Daisuke Akazawa, Katsuki Ono, Hiroshi Ueda, Ryuji Tanimura, Hideo Takahashi, Yoshitaka Yoshizawa, and Ichio Shimada
- Subjects
Magnetic Resonance Spectroscopy ,Platelet Aggregation ,medicine.drug_class ,Platelet Membrane Glycoproteins ,Molecular Dynamics Simulation ,Pharmacology ,Losartan ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Humans ,Platelet ,Platelet activation ,Receptor ,Chemistry ,Antagonist ,Surface Plasmon Resonance ,Receptor antagonist ,Angiotensin II ,Kinetics ,Biochemistry ,cardiovascular system ,Molecular Medicine ,GPVI ,Angiotensin II Type 1 Receptor Blockers ,circulatory and respiratory physiology ,medicine.drug - Abstract
GPVI is a key receptor for collagen-induced platelet activation. Loss or inhibition of GPVI causes only mildly prolonged bleeding times but prevents arterial thrombus formation in animal models. Therefore, GPVI is considered to be a potent target molecule for therapy of thrombotic diseases. Recently, it was reported that the AT(1)-receptor antagonist losartan (DuP-753) and EXP3179 inhibit platelet adhesion and aggregation via GPVI. However, it is still not clear how losartan is associated with inhibition of binding between GPVI and collagen at the molecular level. Here, we show by NMR that losartan directly interacts with the hydrophobic region consisting of strands C' and E in the N-terminal Ig-like domain of GPVI. A reliable GPVI-losartan complex model is presented by using a combination of NMR data and in silico tools. These data indicated that the phenyl group with the tetrazole ring in losartan plays a crucial role in the interaction with GPVI.
- Published
- 2010
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