The Molecular Mechanism of P2Y(1) Receptor Activation

doi:10.1002/anie.201605147

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	The Molecular Mechanism of P2Y(1) Receptor Activation
	Yuan, Shuguang 1; Chan, H. C. Stephen 2; Vogel, Horst 1; Filipek, Slawomir 3,4; Stevens, Raymond C.5,6 ; Palczewski, Krzysztof 7
	2016-08-22
发表期刊	ANGEWANDTE CHEMIE-INTERNATIONAL EDITION (IF:16.1[JCR-2023],16.2[5-Year])
ISSN	1433-7851
卷号	55 期号:35 页码:10331-10335
发表状态	已发表
DOI	10.1002/anie.201605147
摘要	Human purinergic Gprotein-coupled receptor P2Y(1) (P2Y(1)R) is activated by adenosine 5'-diphosphate (ADP) to induce platelet activation and thereby serves as an important antithrombotic drug target. Crystal structures of P2Y(1)R revealed that one ligand (MRS2500) binds to the extracellular vestibule of this GPCR, whereas another (BPTU) occupies the surface between transmembrane (TM) helices TM2 and TM3. We introduced a total of 20 ms all-atom long-timescale molecular dynamic (MD) simulations to inquire why two molecules in completely different locations both serve as antagonists while ADP activates the receptor. Our results indicate that BPTU acts as an antagonist by stabilizing extracellular helix bundles leading to an increase of the lipid order, whereas MRS2500 blocks signaling by occupying the ligand binding site. Both antagonists stabilize an ionic lock within the receptor. However, binding of ADP breaks this ionic lock, forming a continuous water channel that leads to P2Y(1)R activation.
关键词	activation mechanism allosteric ligand GPCR molecular switches P2Y(1)R
收录类别	SCI
语种	英语
资助项目	European Community[FP7-KBBE-2013-613879]
WOS研究方向	Chemistry
WOS类目	Chemistry, Multidisciplinary
WOS记录号	WOS:000383373700025
出版者	WILEY-V C H VERLAG GMBH
WOS关键词	PROTEIN-COUPLED RECEPTORS ; LIGAND-BINDING ; FORCE-FIELD ; SODIUM-IONS ; GPCR ; RECOGNITION ; TRANSMEMBRANE ; ANTAGONISTS ; DISCOVERY ; IDENTIFY
原始文献类型	Article
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/1751
专题	iHuman研究所_特聘教授组_Raymond Stevens组 iHuman研究所
通讯作者	Yuan, Shuguang; Palczewski, Krzysztof
作者单位	1.Ecole Polytech Fed Lausanne EPFL, Lab Phys Chem Polymers & Membranes, Lausanne, Switzerland 2.Univ Bradford, Fac Life Sci, Bradford, W Yorkshire, England 3.Univ Warsaw, Lab Biomodeling, Fac Chem, Warsaw, Poland 4.Univ Warsaw, Biol & Chem Res Ctr, Warsaw, Poland 5.Shanghai Tech Univ, IHuman Inst, Shanghai, Peoples R China 6.Univ Southern Calif, Los Angeles, CA USA 7.Case Western Reserve Univ, Sch Med, Dept Pharmacol, Cleveland, OH 44106 USA
推荐引用方式 GB/T 7714	Yuan, Shuguang,Chan, H. C. Stephen,Vogel, Horst,et al. The Molecular Mechanism of P2Y(1) Receptor Activation[J]. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,2016,55(35):10331-10335.
APA	Yuan, Shuguang,Chan, H. C. Stephen,Vogel, Horst,Filipek, Slawomir,Stevens, Raymond C.,&Palczewski, Krzysztof.(2016).The Molecular Mechanism of P2Y(1) Receptor Activation.ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,55(35),10331-10335.
MLA	Yuan, Shuguang,et al."The Molecular Mechanism of P2Y(1) Receptor Activation".ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 55.35(2016):10331-10335.