title: Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation.
abstract: Adenosine receptors and β-adrenoceptors are G-protein-coupled receptors (GPCRs) that activate intracellular G proteins on binding the agonists adenosine or noradrenaline, respectively. GPCRs have similar structures consisting of seven transmembrane helices that contain well-conserved sequence motifs, indicating that they are probably activated by a common mechanism. Recent structures of β-adrenoceptors highlight residues in transmembrane region 5 that initially bind specifically to agonists rather than to antagonists, indicating that these residues have an important role in agonist-induced activation of receptors. Here we present two crystal structures of the thermostabilized human adenosine A(2A) receptor (A(2A)R-GL31) bound to its endogenous agonist adenosine and the synthetic agonist NECA. The structures represent an intermediate conformation between the inactive and active states, because they share all the features of GPCRs that are thought to be in a fully activated state, except that the cytoplasmic end of transmembrane helix 6 partially occludes the G-protein-binding site. The adenine substituent of the agonists binds in a similar fashion to the chemically related region of the inverse agonist ZM241385 (ref. 8). Both agonists contain a ribose group, not found in ZM241385, which extends deep into the ligand-binding pocket where it makes polar interactions with conserved residues in H7 (Ser 277(7.42) and His 278(7.43); superscripts refer to Ballesteros-Weinstein numbering) and non-polar interactions with residues in H3. In contrast, the inverse agonist ZM241385 does not interact with any of these residues and comparison with the agonist-bound structures indicates that ZM241385 sterically prevents the conformational change in H5 and therefore it acts as an inverse agonist. Comparison of the agonist-bound structures of A(2A)R with the agonist-bound structures of β-adrenoceptors indicates that the contraction of the ligand-binding pocket caused by the inward motion of helices 3, 5 and 7 may be a common feature in the activation of all GPCRs.
authors: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
authors: Guillaume
authors: G
authors: Lebon
authors: Tony
authors: T
authors: Warne
authors: Patricia C
authors: PC
authors: Edwards
authors: Kirstie
authors: K
authors: Bennett
authors: Christopher J
authors: CJ
authors: Langmead
authors: Andrew G W
authors: AG
authors: Leslie
authors: Christopher G
authors: CG
authors: Tate
references: J Mol Biol. 2009 Jul 10;390(2):262-77
references: 19422831
references: J Am Chem Soc. 2010 Aug 25;132(33):11443-5
references: 20669948
references: Science. 2011 Apr 15;332(6027):322-7
references: 21393508
references: Acta Crystallogr D Biol Crystallogr. 2011 May;67(Pt 5):463-70
references: 21543849
references: Science. 2008 Nov 21;322(5905):1211-7
references: 18832607
references: Science. 2000 Aug 4;289(5480):739-45
references: 10926528
references: Neuropharmacology. 2011 Jan;60(1):36-44
references: 20624408
references: Pharmacol Rev. 2011 Mar;63(1):1-34
references: 21303899
references: Nature. 2011 Jan 13;469(7329):236-40
references: 21228876
references: Curr Top Med Chem. 2010;10(10):993-1018
references: 20370656
references: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2288-94
references: 15572783
references: Nature. 2008 Jul 10;454(7201):183-7
references: 18563085
references: Acta Crystallogr D Biol Crystallogr. 2006 Jan;62(Pt 1):72-82
references: 16369096
references: Nucleic Acids Res. 2007 Jul;35(Web Server issue):W375-83
references: 17452350
references: Nature. 2007 Nov 15;450(7168):383-7
references: 17952055
references: Science. 2010 Nov 19;330(6007):1066-71
references: 20929726
references: Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
references: 15299926
references: Biochim Biophys Acta. 2003 Feb 17;1610(1):133-40
references: 12586387
references: J Mol Biol. 1994 May 20;238(5):777-93
references: 8182748
references: Mol Pharmacol. 2002 Feb;61(2):455-62
references: 11809871
references: Science. 2007 Nov 23;318(5854):1258-65
references: 17962520
references: Nature. 2011 Jan 13;469(7329):241-4
references: 21228877
references: Science. 2010 Nov 19;330(6007):1091-5
references: 21097933
references: Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):877-82
references: 18192400
references: Nat Rev Mol Cell Biol. 2008 Jan;9(1):60-71
references: 18043707
references: Trends Biochem Sci. 2009 Nov;34(11):540-52
references: 19836958
references: Nature. 2011 Jan 13;469(7329):175-80
references: 21228869
references: Acta Crystallogr A. 1991 Mar 1;47 ( Pt 2):110-9
references: 2025413
references: Fundam Clin Pharmacol. 2005 Feb;19(1):45-56
references: 15660959
references: J Mol Biol. 2004 Nov 5;343(5):1409-38
references: 15491621
references: Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
references: 20383002
references: Acta Crystallogr D Biol Crystallogr. 2006 Jan;62(Pt 1):48-57
references: 16369093
references: Anal Biochem. 1973 Dec;56(2):502-14
references: 4128882
references: Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9501-6
references: 19470481
references: Nature. 2008 Jul 24;454(7203):486-91
references: 18594507
references: Nature. 2009 May 21;459(7245):356-63
references: 19458711
references: J Med Chem. 2003 Nov 6;46(23):4847-59
references: 14584936
references: J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
references: 19461840
references: Trends Pharmacol Sci. 2007 Aug;28(8):397-406
references: 17629961
references: Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10744-9
references: 18664584
references: Br J Pharmacol. 2010 Mar;159(5):1022-38
references: 20132209
references: Nature. 2008 Sep 25;455(7212):497-502
references: 18818650
references: Eur J Biochem. 2002 Jan;269(1):82-92
references: 11784301