Structural basis for platelet antiaggregation by angiotensin II type 1 receptor antagonist losartan (DuP-753) via glycoprotein VI.
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.
Ono
Katsuki
K
Japan Biological Informatics Consortium (JBIC), Aomi 2-41-6, Tokyo 135-0064, Japan.
Ueda
Hiroshi
H
Yoshizawa
Yoshitaka
Y
Akazawa
Daisuke
D
Tanimura
Ryuji
R
Shimada
Ichio
I
Takahashi
Hideo
H
D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D019808:Losartan / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
D047228:Angiotensin II Type 1 Receptor Blockers; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D019808:Losartan