Nucleotides Acting at P2Y Receptors: Connecting Structure and Function

doi:10.1124/mol.114.095711

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	Nucleotides Acting at P2Y Receptors: Connecting Structure and Function
	Jacobson, Kenneth A.2; Paoletta, Silvia 2; Katritch, Vsevolod 3; Wu, Beili1 ; Gao, Zhan-Guo 2; Zhao, Qiang1 ; Stevens, Raymond C.3; Kiselev, Evgeny 2
刊名	MOLECULAR PHARMACOLOGY
	2015-08
卷号	88 期号:2 页码:220-230
ISSN号	0026-895X
DOI	10.1124/mol.114.095711
文献子类	Review
英文摘要	Eight G protein-coupled P2Y receptor (P2YR) subtypes are important physiologic mediators. The human P2YRs are fully activated by ATP (P2Y(2) and P2Y(11)), ADP (P2Y(1), P2Y(12), and P2Y(13)), UTP (P2Y(2) and P2Y(4)), UDP (P2Y(6) and P2Y(14)), and UDP glucose (P2Y(14)). Their structural elucidation is progressing rapidly. The X-ray structures of three ligand complexes of the G(i)-coupled P2Y(12)R and two of the G(q)-coupled P2Y(1)Rs were recently determined and will be especially useful in structure-based ligand design at two P2YR subfamilies. These high-resolution structures, which display unusual binding site features, complement mutagenesis studies for probing ligand recognition and activation. The structural requirements for nucleotide agonist recognition at P2YRs are relatively permissive with respect to the length of the phosphate moiety, but less so with respect to base recognition. Nucleotide-like antagonists and partial agonists are also known for P2Y(1), P2Y(2), P2Y(4), and P2Y(12)Rs. Each P2YR subtype has the ability to be activated by structurally bifunctional agonists, such as dinucleotides, typically, dinucleoside triphosphates or tetraphosphates, and nucleoside polyphosphate sugars (e.g., UDP glucose) as well as the more conventional mononucleotide agonists. A range of dinucleoside polyphosphates, from triphosphates to higher homologs, occurs naturally. Earlier modeling predictions of the P2YRs were not very accurate, but recent findings have provided much detailed structural insight into this receptor family to aid in the rational design of new drugs.
资助项目	NIGMS NIH HHS[U54 GM094618] ; NIDDK NIH HHS[Z01 DK031126] ; NIDDK NIH HHS[Z01-DK031126-08] ; Intramural NIH HHS[ZIA DK031116-27]
WOS关键词	HUMAN P2Y(12) RECEPTOR ; URIDINE ADENOSINE-TETRAPHOSPHATE ; DINUCLEOSIDE POLYPHOSPHATES ; PLATELET-AGGREGATION ; ADP RECEPTOR ; DIADENOSINE POLYPHOSPHATES ; MUTATIONAL ANALYSIS ; URACIL NUCLEOTIDES ; SELECTIVE AGONISTS ; CYSTIC-FIBROSIS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000357092600001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276462]
专题	药物靶标结构与功能中心
通讯作者	Jacobson, Kenneth A.
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 200031, Peoples R China 2.NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA; 3.Univ So Calif, Dana & David Dornsife Sch Letters Arts & Sci, Bridge Inst, Los Angeles, CA USA;
推荐引用方式 GB/T 7714	Jacobson, Kenneth A.,Paoletta, Silvia,Katritch, Vsevolod,et al. Nucleotides Acting at P2Y Receptors: Connecting Structure and Function[J]. MOLECULAR PHARMACOLOGY,2015,88(2):220-230.
APA	Jacobson, Kenneth A..,Paoletta, Silvia.,Katritch, Vsevolod.,Wu, Beili.,Gao, Zhan-Guo.,...&Kiselev, Evgeny.(2015).Nucleotides Acting at P2Y Receptors: Connecting Structure and Function.MOLECULAR PHARMACOLOGY,88(2),220-230.
MLA	Jacobson, Kenneth A.,et al."Nucleotides Acting at P2Y Receptors: Connecting Structure and Function".MOLECULAR PHARMACOLOGY 88.2(2015):220-230.