title: Nucleotides Acting at P2Y Receptors: Connecting Structure and Function.
abstract: Eight G protein-coupled P2Y receptor (P2YR) subtypes are important physiologic mediators. The human P2YRs are fully activated by ATP (P2Y2 and P2Y11), ADP (P2Y1, P2Y12, and P2Y13), UTP (P2Y2 and P2Y4), UDP (P2Y6 and P2Y14), and UDP glucose (P2Y14). Their structural elucidation is progressing rapidly. The X-ray structures of three ligand complexes of the Gi-coupled P2Y12R and two of the Gq-coupled P2Y1Rs 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 P2Y1, P2Y2, P2Y4, and P2Y12Rs. 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.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (K.A.J., S.P., Z.-G.G., E.K.); The Bridge Institute, Dana and David Dornsife School of Letters, Arts, and Sciences, University of Southern California, Los Angeles, California (V.K., R.C.S.); and Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (B.W., Q.Z.) kajacobs@helix.nih.gov.
authors.forename: Kenneth A
authors.identifier: http://orcid.org/0000-0001-8104-1493
authors.initials: KA
authors.lastname: Jacobson
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (K.A.J., S.P., Z.-G.G., E.K.); The Bridge Institute, Dana and David Dornsife School of Letters, Arts, and Sciences, University of Southern California, Los Angeles, California (V.K., R.C.S.); and Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (B.W., Q.Z.).
authors.forename: Silvia
authors.initials: S
authors.lastname: Paoletta
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (K.A.J., S.P., Z.-G.G., E.K.); The Bridge Institute, Dana and David Dornsife School of Letters, Arts, and Sciences, University of Southern California, Los Angeles, California (V.K., R.C.S.); and Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (B.W., Q.Z.).
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Katritch
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (K.A.J., S.P., Z.-G.G., E.K.); The Bridge Institute, Dana and David Dornsife School of Letters, Arts, and Sciences, University of Southern California, Los Angeles, California (V.K., R.C.S.); and Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (B.W., Q.Z.).
authors.forename: Beili
authors.initials: B
authors.lastname: Wu
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (K.A.J., S.P., Z.-G.G., E.K.); The Bridge Institute, Dana and David Dornsife School of Letters, Arts, and Sciences, University of Southern California, Los Angeles, California (V.K., R.C.S.); and Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (B.W., Q.Z.).
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (K.A.J., S.P., Z.-G.G., E.K.); The Bridge Institute, Dana and David Dornsife School of Letters, Arts, and Sciences, University of Southern California, Los Angeles, California (V.K., R.C.S.); and Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (B.W., Q.Z.).
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (K.A.J., S.P., Z.-G.G., E.K.); The Bridge Institute, Dana and David Dornsife School of Letters, Arts, and Sciences, University of Southern California, Los Angeles, California (V.K., R.C.S.); and Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (B.W., Q.Z.).
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (K.A.J., S.P., Z.-G.G., E.K.); The Bridge Institute, Dana and David Dornsife School of Letters, Arts, and Sciences, University of Southern California, Los Angeles, California (V.K., R.C.S.); and Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China (B.W., Q.Z.).
authors.forename: Evgeny
authors.initials: E
authors.lastname: Kiselev
mesh_terms: D001665:Binding Sites; D006801:Humans; D008958:Models, Molecular; D009711:Nucleotides / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D058912:Purinergic P2Y Receptor Agonists / Q000737:chemistry / Q000378:metabolism*; D058470:Receptors, Purinergic P2Y / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D009711:Nucleotides; D058912:Purinergic P2Y Receptor Agonists; D058470:Receptors, Purinergic P2Y
references.citation: Proc Natl Acad Sci U S A. 2014 Nov 4;111(44):15821-6
references.pmid: 25341729
references.citation: FEBS Lett. 1993 Jun 14;324(2):219-25
references.pmid: 8508924
references.citation: J Med Chem. 2003 Nov 6;46(23):4974-87
references.pmid: 14584948
references.citation: Bioorg Med Chem. 2015 Jul 15;23(14):4056-64
references.pmid: 25868749
references.citation: Mol Pharmacol. 2003 Oct;64(4):785-95
references.pmid: 14500734
references.citation: J Med Chem. 2007 Jul 12;50(14):3229-41
references.pmid: 17564423
references.citation: Nature. 2013 Dec 5;504(7478):101-6
references.pmid: 24256733
references.citation: Adv Pharmacol. 2011;61:263-99
references.pmid: 21586362
references.citation: Bioorg Med Chem Lett. 2009 Jun 1;19(11):3002-5
references.pmid: 19419868
references.citation: J Med Chem. 2010 Jun 10;53(11):4488-501
references.pmid: 20446735
references.citation: Mol Pharmacol. 2013 Apr;83(4):759-69
references.pmid: 23253448
references.citation: J Med Chem. 2010 Jan 14;53(1):471-80
references.pmid: 19902968
references.citation: Pflugers Arch. 2006 Aug;452(5):563-72
references.pmid: 16688466
references.citation: Biochem Pharmacol. 2008 Nov 15;76(10):1201-13
references.pmid: 18809389
references.citation: Purinergic Signal. 2013 Mar;9(1):59-66
references.pmid: 22892887
references.citation: J Biol Chem. 2001 Apr 13;276(15):11939-48
references.pmid: 11114308
references.citation: Biochem Pharmacol. 2008 Mar 15;75(6):1341-7
references.pmid: 18199424
references.citation: Drugs. 2013 Oct;73(15):1681-709
references.pmid: 24114622
references.citation: Nature. 2014 May 1;509(7498):115-8
references.pmid: 24670650
references.citation: Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2370-3
references.pmid: 1549600
references.citation: Nature. 1994 Jan 13;367(6459):186-8
references.pmid: 8114917
references.citation: J Biol Chem. 2000 Apr 14;275(15):10767-71
references.pmid: 10753868
references.citation: Wiley Interdiscip Rev Membr Transp Signal. 2012 Sep 12;1(6):null
references.pmid: 23336097
references.citation: Clin Ophthalmol. 2014 Jan 30;8:327-34
references.pmid: 24511227
references.citation: J Med Chem. 2004 Oct 21;47(22):5393-404
references.pmid: 15481977
references.citation: Pharmacol Ther. 2000 Aug-Sep;87(2-3):103-15
references.pmid: 11007994
references.citation: J Thromb Haemost. 2012 Dec;10(12):2573-80
references.pmid: 23083103
references.citation: J Med Chem. 2013 Feb 28;56(4):1704-14
references.pmid: 23368907
references.citation: J Biol Chem. 1995 Mar 3;270(9):4185-8
references.pmid: 7876172
references.citation: Blood. 2012 Nov 22;120(22):4432-40
references.pmid: 22995898
references.citation: Eur J Pharmacol. 2001 Nov 2;430(2-3):203-10
references.pmid: 11711032
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16359-64
references.pmid: 17913880
references.citation: J Pharmacol Exp Ther. 2002 May;301(2):705-13
references.pmid: 11961076
references.citation: J Med Chem. 2008 Feb 28;51(4):1007-25
references.pmid: 18232657
references.citation: J Biol Chem. 2006 Oct 20;281(42):31419-29
references.pmid: 16926152
references.citation: Pharmacol Rev. 2006 Sep;58(3):281-341
references.pmid: 16968944
references.citation: Exp Eye Res. 2012 Aug;101:49-55
references.pmid: 22677090
references.citation: Br J Pharmacol. 2009 Aug;157(7):1142-53
references.pmid: 19563527
references.citation: Bioorg Med Chem. 2008 Jun 15;16(12):6319-32
references.pmid: 18514530
references.citation: Am J Respir Crit Care Med. 2007 Aug 15;176(4):362-9
references.pmid: 17446337
references.citation: Exp Eye Res. 2011 Mar;92(3):221-6
references.pmid: 21147104
references.citation: Purinergic Signal. 2012 Sep;8(3):437-502
references.pmid: 22555564
references.citation: Mol Pharmacol. 2013 Jan;83(1):256-66
references.pmid: 23093496
references.citation: Bioorg Med Chem Lett. 2007 Nov 1;17(21):6013-8
references.pmid: 17827008
references.citation: FEBS J. 2012 Jan;279(1):180-91
references.pmid: 22044483
references.citation: Mol Pharmacol. 2009 Dec;76(6):1341-8
references.pmid: 19759354
references.citation: Trends Biochem Sci. 2014 May;39(5):233-44
references.pmid: 24767681
references.citation: Drug Discov Today. 2010 Jul;15(13-14):570-8
references.pmid: 20594935
references.citation: Mol Pharmacol. 2001 Sep;60(3):432-9
references.pmid: 11502873
references.citation: Proc Natl Acad Sci U S A. 1976 Nov;73(11):3984-8
references.pmid: 1069282
references.citation: Cell Calcium. 2009 Oct;46(4):263-72
references.pmid: 19748117
references.citation: Nature. 2014 May 1;509(7498):119-22
references.pmid: 24784220
references.citation: J Med Chem. 2011 Apr 28;54(8):2878-90
references.pmid: 21417463
references.citation: Curr Med Chem. 2006;13(3):289-312
references.pmid: 16475938
references.citation: Chembiochem. 2012 Nov 5;13(16):2384-91
references.pmid: 22997138
references.citation: J Med Chem. 2009 May 14;52(9):2762-75
references.pmid: 19419204
references.citation: Biochem Pharmacol. 2004 Nov 15;68(10):2075-86
references.pmid: 15476678
references.citation: Biochem Pharmacol. 2013 Apr 1;85(7):991-8
references.pmid: 23333427
references.citation: J Med Chem. 2014 May 8;57(9):3874-83
references.pmid: 24712832
references.citation: Nature. 2015 Apr 16;520(7547):317-21
references.pmid: 25822790
references.citation: J Pharmacol Exp Ther. 2002 Sep;302(3):871-80
references.pmid: 12183642
references.citation: Biochem Biophys Res Commun. 2012 Jan 20;417(3):1035-40
references.pmid: 22214933
references.citation: Structure. 2012 Nov 7;20(11):1948-59
references.pmid: 23041369
references.citation: Br J Pharmacol. 1996 Aug;118(8):1959-64
references.pmid: 8864529
references.citation: Purinergic Signal. 2005 Jun;1(2):183-91
references.pmid: 18404503
references.citation: J Med Chem. 2014 Jul 24;57(14):6150-64
references.pmid: 24931384
references.citation: Bioorg Med Chem. 2009 Jul 15;17(14):5298-311
references.pmid: 19502066
references.citation: J Bacteriol. 2010 Jun;192(12):3011-23
references.pmid: 20154123
references.citation: Biochemistry. 1999 Mar 23;38(12):3498-507
references.pmid: 10090736
references.citation: Br J Pharmacol. 1995 Sep;116(1):1619-27
references.pmid: 8564228
references.citation: J Med Chem. 2011 Jun 23;54(12):4018-33
references.pmid: 21528910
references.citation: PLoS One. 2014;9(4):e94780
references.pmid: 24722456
references.citation: Prog Brain Res. 1999;120:397-409
references.pmid: 10551014
references.citation: Neurosci Lett. 2014 Aug 22;578:80-4
references.pmid: 24970757
references.citation: Thromb Res. 2010 Feb;125(2):159-65
references.pmid: 19945153
references.citation: J Thromb Haemost. 2009 Sep;7(9):1556-65
references.pmid: 19552634
references.citation: J Med Chem. 2013 Jun 27;56(12):4938-52
references.pmid: 23751098
references.citation: J Med Chem. 2012 Jan 12;55(1):437-48
references.pmid: 22107038
references.citation: Biochem J. 2007 Jul 15;405(2):277-86
references.pmid: 17338680
references.citation: Biochem Biophys Res Commun. 2013 Jun 28;436(2):199-203
references.pmid: 23726915
references.citation: Mol Pharmacol. 2000 May;57(5):926-31
references.pmid: 10779375
references.citation: J Thromb Haemost. 2004 Nov;2(11):1980-8
references.pmid: 15550030
references.citation: Comb Chem High Throughput Screen. 2008 Jul;11(6):410-9
references.pmid: 18673269
references.citation: Eur J Pharmacol. 2010 Oct 10;644(1-3):10-6
references.pmid: 20599922
references.citation: J Biol Chem. 2004 Mar 19;279(12):11456-64
references.pmid: 14670966
references.citation: Mol Pharmacol. 1996 Nov;50(5):1323-9
references.pmid: 8913364