title: Evolution-guided discovery and recoding of allosteric pathway specificity determinants in psychoactive bioamine receptors.
abstract: G protein-coupled receptors for dopamine and serotonin control signaling pathways targeted by many psychoactive drugs. A puzzle is how receptors with similar functions and nearly identical binding site structures, such as D2 dopamine receptors and 5-HT2A serotonin receptors, could evolve a mechanism that discriminates stringently in their cellular responses between endogenous neurotransmitters. We used the Difference Evolutionary Trace (Difference-ET) and residue-swapping to uncover two distinct sets of specificity-determining sequence positions. One at the ligand-binding pocket determines the relative affinities for these two ligands, and a distinct, surprising set of positions outside the binding site determines whether a bound ligand can trigger the conformational rearrangement leading to G protein activation. Thus one site specifies affinity while the other encodes a filter for efficacy. These findings demonstrate that allosteric pathways linking distant interactions via alternate conformational states enforce specificity independently of the ligand-binding site, such that either one may be rationally rekeyed to different ligands. The conversion of a dopamine receptor effectively into a serotonin receptor illustrates the plasticity of GPCR signaling during evolution, or in pathological states, and suggests new approaches to drug discovery, targeting both classes of sites.
authors.affiliation: Verna and Marrs Mclean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Gustavo J
authors.initials: GJ
authors.lastname: Rodriguez
authors.forename: Rong
authors.initials: R
authors.lastname: Yao
authors.forename: Olivier
authors.initials: O
authors.lastname: Lichtarge
authors.forename: Theodore G
authors.initials: TG
authors.lastname: Wensel
mesh_terms: D000494:Allosteric Regulation / Q000235:genetics*; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D019143:Evolution, Molecular; D005453:Fluorescence; D006801:Humans; D008958:Models, Molecular; D016296:Mutagenesis; D011487:Protein Conformation; D011619:Psychotropic Drugs / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D011619:Psychotropic Drugs; D043562:Receptors, G-Protein-Coupled
references.citation: Mol Pharmacol. 2005 Nov;68(5):1484-95
references.pmid: 16113085
references.citation: J Biol Chem. 2006 Jan 13;281(2):1261-73
references.pmid: 16280323
references.citation: Mol Pharmacol. 1998 Aug;54(2):435-44
references.pmid: 9687586
references.citation: PLoS One. 2008 May 07;3(5):e2136
references.pmid: 18461181
references.citation: J Pharmacol Exp Ther. 2007 Apr;321(1):298-307
references.pmid: 17204745
references.citation: Nature. 2008 Jul 24;454(7203):486-91
references.pmid: 18594507
references.citation: Nat Struct Mol Biol. 2007 Apr;14(4):301-7
references.pmid: 17351632
references.citation: Annu Rev Physiol. 2007;69:483-510
references.pmid: 17305471
references.citation: J Mol Biol. 2010 Mar 12;396(5):1451-73
references.pmid: 20036248
references.citation: Arch Pharm Res. 2008 Apr;31(4):474-81
references.pmid: 18449505
references.citation: J Mol Biol. 2004 Mar 5;336(5):1265-82
references.pmid: 15037084
references.citation: Trends Pharmacol Sci. 2007 Aug;28(8):382-9
references.pmid: 17629965
references.citation: J Biol Chem. 2002 Oct 25;277(43):40989-96
references.pmid: 12167654
references.citation: Nat Struct Biol. 2001 Mar;8(3):234-7
references.pmid: 11224568
references.citation: J Mol Biol. 2002 Feb 8;316(1):139-54
references.pmid: 11829509
references.citation: Nature. 1996 Sep 26;383(6598):347-50
references.pmid: 8848049
references.citation: Adv Pharmacol. 1998;42:412-5
references.pmid: 9327927
references.citation: Biophys J. 2008 Mar 15;94(6):2027-42
references.pmid: 18065472
references.citation: J Biol Chem. 2004 Feb 27;279(9):8126-32
references.pmid: 14660595
references.citation: Pharmacol Ther. 2004 Dec;104(3):233-44
references.pmid: 15556676
references.citation: Science. 2008 Nov 21;322(5905):1211-7
references.pmid: 18832607
references.citation: Trends Pharmacol Sci. 2007 Aug;28(8):416-22
references.pmid: 17644195
references.citation: Mol Pharmacol. 1999 Dec;56(6):1116-26
references.pmid: 10570038
references.citation: Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10355-9
references.pmid: 7937955
references.citation: Science. 2000 Aug 4;289(5480):739-45
references.pmid: 10926528
references.citation: Mol Pharmacol. 2006 Jan;69(1):185-94
references.pmid: 16236817
references.citation: J Mol Biol. 2003 Aug 1;331(1):263-79
references.pmid: 12875851
references.citation: J Mol Biol. 2003 Feb 7;326(1):255-61
references.pmid: 12547207
references.citation: Science. 2007 Nov 23;318(5854):1258-65
references.pmid: 17962520
references.citation: Curr Med Chem. 2009;16(8):1017-27
references.pmid: 19275609
references.citation: J Biol Chem. 2005 Jun 10;280(23):22165-71
references.pmid: 15817484
references.citation: J Mol Biol. 1996 Mar 29;257(2):342-58
references.pmid: 8609628
references.citation: Mol Pharmacol. 2010 Mar;77(3):405-15
references.pmid: 20038610
references.citation: Bioinformatics. 2009 Jun 1;25(11):1426-7
references.pmid: 19307237
references.citation: Mol Pharmacol. 2007 Apr;71(4):959-64
references.pmid: 17192495
references.citation: Endocr Rev. 2000 Feb;21(1):90-113
references.pmid: 10696571
references.citation: J Pharmacol Exp Ther. 2007 Jan;320(1):1-13
references.pmid: 16803859
references.citation: Science. 1996 Nov 1;274(5288):768-70
references.pmid: 8864113
references.citation: Proteins. 2006 Sep 1;64(4):1046-57
references.pmid: 16835908
references.citation: Nat Rev Drug Discov. 2006 Dec;5(12):993-6
references.pmid: 17139284
references.citation: Biochemistry. 2008 Oct 21;47(42):11013-23
references.pmid: 18821775
references.citation: Nat Rev Drug Discov. 2002 Feb;1(2):103-10
references.pmid: 12120091
references.citation: Biochemistry. 2000 Oct 10;39(40):12190-9
references.pmid: 11015197
references.citation: Curr Top Med Chem. 2006;6(17):1845-59
references.pmid: 17017961
references.citation: Traffic. 2009 Aug;10(8):1019-33
references.pmid: 19515093
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3815-20
references.pmid: 14999101