title: The receptor concept in 3D: from hypothesis and metaphor to GPCR-ligand structures.
abstract: The first mentioning of the word "receptor" for the structure with which a bioactive compound should react for obtaining its specific influence on a physiological system goes back to the years around 1900. The receptor concept was adapted from the lock and key theory for the enzyme substrate and blockers interactions. Through the years the concept, in the beginning rather being a metaphor, not a model, was refined and became reality in recent years. Not only the structures of receptors were elucidated, also the receptor machineries were unraveled. Following a brief historical review we will describe how the recent breakthroughs in the experimental determination of G protein-coupled receptor (GPCR) crystal structures can be complemented by computational modeling, medicinal chemistry, biochemical, and molecular pharmacological studies to obtain new insights into the molecular determinants of GPCR-ligand binding and activation. We will furthermore discuss how this information can be used for structure-based discovery of novel GPCR ligands that bind specific (allosteric) binding sites with desired effects on GPCR functional activity.
authors.affiliation: Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Kooistra
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
authors.forename: Henk
authors.initials: H
authors.lastname: Timmerman
mesh_terms: D008024:Ligands; D008956:Models, Chemical; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled
references.citation: Nature. 2013 Dec 5;504(7478):101-6
references.pmid: 24256733
references.citation: Nature. 2013 May 2;497(7447):137-41
references.pmid: 23604254
references.citation: Annu Rev Pharmacol Toxicol. 2012;52:153-78
references.pmid: 21910627
references.citation: Med Hist. 2003 Jul;47(3):332-56
references.pmid: 12905918
references.citation: Nature. 2014 Jul 31;511(7511):557-62
references.pmid: 25042998
references.citation: Trends Pharmacol Sci. 2011 Nov;32(11):637-43
references.pmid: 21903279
references.citation: Biochem Soc Trans. 2013 Feb 1;41(1):159-65
references.pmid: 23356277
references.citation: Nature. 2013 Nov 14;503(7475):295-9
references.pmid: 24121438
references.citation: J Med Chem. 2011 Dec 8;54(23):8195-206
references.pmid: 22007643
references.citation: Neuropharmacology. 2011 Jan;60(1):24-35
references.pmid: 20637785
references.citation: Nature. 2011 Jun 22;475(7354):65-70
references.pmid: 21697825
references.citation: Angew Chem Int Ed Engl. 2013 Jan 7;52(2):508-16
references.pmid: 23225228
references.citation: Nature. 2013 May 16;497(7449):338-43
references.pmid: 23636324
references.citation: Cell. 2013 Jan 31;152(3):532-42
references.pmid: 23374348
references.citation: J Med Chem. 2008 Sep 11;51(17):5297-303
references.pmid: 18707087
references.citation: Science. 2014 Apr 4;344(6179):58-64
references.pmid: 24603153
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6843-8
references.pmid: 19342484
references.citation: Nature. 2013 May 2;497(7447):142-6
references.pmid: 23604253
references.citation: Structure. 2012 May 9;20(5):841-9
references.pmid: 22579251
references.citation: J Med Chem. 2008 Aug 28;51(16):4978-85
references.pmid: 18680279
references.citation: Science. 2012 Jul 13;337(6091):232-6
references.pmid: 22798613
references.citation: Nature. 2008 Jul 10;454(7201):183-7
references.pmid: 18563085
references.citation: PLoS One. 2014 Mar 24;9(3):e92727
references.pmid: 24663151
references.citation: J Med Chem. 2012 Mar 8;55(5):1898-903
references.pmid: 22220592
references.citation: Nat Chem Biol. 2011 Sep 18;7(11):769-78
references.pmid: 21926995
references.citation: J Chem Inf Model. 2009 Jan;49(1):84-96
references.pmid: 19125657
references.citation: Proc Natl Acad Sci U S A. 2014 Feb 4;111(5):1825-30
references.pmid: 24449856
references.citation: Science. 1997 Sep 12;277(5332):1676-81
references.pmid: 9287223
references.citation: Nat Commun. 2014;5:3309
references.pmid: 24525480
references.citation: Br J Pharmacol. 2014 Jul;171(14):3364-75
references.pmid: 24628038
references.citation: Trends Pharmacol Sci. 2004 Aug;25(8):413-22
references.pmid: 15276710
references.citation: Nature. 2013 Jul 25;499(7459):444-9
references.pmid: 23863937
references.citation: J Biol Chem. 2004 Jan 2;279(1):686-91
references.pmid: 14559905
references.citation: Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):E655-62
references.pmid: 24453215
references.citation: Science. 2010 Nov 19;330(6007):1066-71
references.pmid: 20929726
references.citation: Drug Discov Today. 2009 Jul;14(13-14):630-46
references.pmid: 19443265
references.citation: Science. 2012 Mar 2;335(6072):1106-10
references.pmid: 22267580
references.citation: ACS Chem Biol. 2013 May 17;8(5):1018-26
references.pmid: 23485065
references.citation: J Comput Aided Mol Des. 1995 Aug;9(4):319-30
references.pmid: 8523041
references.citation: Nature. 2013 Jul 25;499(7459):438-43
references.pmid: 23863939
references.citation: J Chem Inf Model. 2007 Jan-Feb;47(1):195-207
references.pmid: 17238265
references.citation: J Chem Inf Model. 2013 Oct 28;53(10):2701-14
references.pmid: 23971943
references.citation: Nature. 2014 Aug 14;512(7513):218-222
references.pmid: 25043026
references.citation: J Med Chem. 2012 Mar 8;55(5):1904-9
references.pmid: 22250781
references.citation: Annu Rev Biophys Biomol Struct. 2003;32:375-97
references.pmid: 12574068
references.citation: J Med Chem. 2010 May 13;53(9):3748-55
references.pmid: 20405927
references.citation: Br J Pharmacol. 2013 Sep;170(1):101-26
references.pmid: 23713847
references.citation: Science. 2013 May 3;340(6132):610-4
references.pmid: 23519210
references.citation: Science. 2013 Sep 20;341(6152):1387-90
references.pmid: 24030490
references.citation: ACS Med Chem Lett. 2013 Oct 10;4(10):1005-1010
references.pmid: 24454993
references.citation: Nature. 2013 Feb 14;494(7436):185-94
references.pmid: 23407534
references.citation: Nature. 2011 Jul 19;477(7366):549-55
references.pmid: 21772288
references.citation: Mol Pharmacol. 2013 Dec;84(6):794-807
references.pmid: 24021214
references.citation: Mol Biosyst. 2014 Jul;10(7):1958-67
references.pmid: 24820411
references.citation: J Med Chem. 2013 Nov 14;56(21):8746-56
references.pmid: 24088171
references.citation: Nat Chem Biol. 2012 Jul 18;8(8):670-3
references.pmid: 22810761
references.citation: Pharmacol Ther. 2014 Jul;143(1):51-60
references.pmid: 24561131
references.citation: Mol Pharmacol. 2011 Feb;79(2):262-9
references.pmid: 21081645
references.citation: Science. 2000 Aug 4;289(5480):739-45
references.pmid: 10926528
references.citation: Science. 2007 Nov 23;318(5854):1258-65
references.pmid: 17962520
references.citation: Br J Pharmacol. 2013 Sep;170(1):78-88
references.pmid: 23351115
references.citation: Nature. 2011 Jan 13;469(7329):175-80
references.pmid: 21228869
references.citation: Bioorg Med Chem Lett. 2013 May 1;23(9):2663-70
references.pmid: 23558237
references.citation: Proc Natl Acad Sci U S A. 2014 Mar 25;111(12):4614-9
references.pmid: 24619092
references.citation: Adv Exp Med Biol. 2014;796:15-33
references.pmid: 24158799
references.citation: J Mol Biol. 1990 Jun 20;213(4):899-929
references.pmid: 2359127
references.citation: Nature. 2012 Dec 13;492(7428):215-20
references.pmid: 23235874
references.citation: Curr Opin Struct Biol. 2012 Aug;22(4):482-90
references.pmid: 22480933
references.citation: J Biol Chem. 1999 Oct 15;274(42):29994-30000
references.pmid: 10514483
references.citation: Nature. 2010 Jan 7;463(7277):108-12
references.pmid: 20054398
references.citation: PLoS Comput Biol. 2012;8(8):e1002649
references.pmid: 22916005
references.citation: J Chem Inf Model. 2013 Jul 22;53(7):1700-13
references.pmid: 23725291
references.citation: Nature. 2014 May 1;509(7498):115-8
references.pmid: 24670650
references.citation: Nat Chem Biol. 2005 Jul;1(2):98-103
references.pmid: 16408006
references.citation: J Med Chem. 2011 Dec 8;54(23):8136-47
references.pmid: 22003888
references.citation: Adv Exp Med Biol. 2014;796:129-57
references.pmid: 24158804
references.citation: Curr Opin Cell Biol. 2014 Apr;27:25-31
references.pmid: 24680427
references.citation: Nature. 2011 May 18;474(7352):521-5
references.pmid: 21593763
references.citation: Drug Discov Today. 2013 Apr;18(7-8):323-30
references.pmid: 23266367
references.citation: Nature. 2012 Dec 20;492(7429):387-92
references.pmid: 23222541
references.citation: Proc Natl Acad Sci U S A. 2012 Apr 3;109(14):5517-22
references.pmid: 22431600
references.citation: J Med Chem. 2010 Feb 25;53(4):1799-809
references.pmid: 20095623
references.citation: FASEB J. 2001 Mar;15(3):598-611
references.pmid: 11259378
references.citation: J Chem Inf Model. 2012 Dec 21;52(12):3308-24
references.pmid: 23140085
references.citation: Nature. 2014 May 1;509(7498):119-22
references.pmid: 24784220
references.citation: Methods Enzymol. 2013;522:279-336
references.pmid: 23374191
references.citation: Nature. 2013 Oct 24;502(7472):575-579
references.pmid: 24056936
references.citation: Nature. 2014 Feb 13;506(7487):191-6
references.pmid: 24413399
references.citation: Prog Med Chem. 2014;53:1-63
references.pmid: 24418607
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13118-23
references.pmid: 21778406
references.citation: Annu Rev Pharmacol Toxicol. 2013;53:531-56
references.pmid: 23140243
references.citation: Structure. 2013 Dec 3;21(12):2175-85
references.pmid: 24210756
references.citation: Trends Pharmacol Sci. 2014 Jan;35(1):12-22
references.pmid: 24359917
references.citation: J Anat Physiol. 1868;2(2):224-42
references.pmid: 17230757
references.citation: Mol Pharmacol. 2012 Sep;82(3):361-71
references.pmid: 22695719