GPCR Structure: Human PAR1 Receptor
Another GPCR structure, this time that of human Protease Activated Receptor-1 also known as the thrombin receptor (PAR1) receptor, complexed with the late-stage clinical candidate antagonist vorapaxar (SCH-530348). This brings the total number of sequence distinct GPCRs now known structurally to 18. The PDB code is 3vw7. This structure helps understand the mechanism of regulation of the binding of the thrombin cleaved N-terminus involved in receptor activation.
Update: I just looked at the tracking page at Scripps - and there's a lot of near term exciting stuff by the looks of it - 5HT2B and 5HT1C in refinement - these will be great for exploring polypharmacology of many centrally acting drugs, and glucagon receptor - the first class 2 GPCR (Heptares have announced that they have the structure of a type 2 as well, but with no plans to publish). We do live in interesting times!
The link to the paper is here.
%A C. Zhang %A Y. Srinivasan %A D.H. Arlow %A J.J. Fung %A D. Palmer %A Y. Zheng %A H.F. Green %A A. Pandey %A R.O. Dror %A D.E. Shaw %A W.I. Weis %A S.R. Coughlin %A B.K. Kobilka %T High-resolution crystal structure of human protease-activated receptor 1 %J Nature %D 2012 %O http://dx.doi.org/10.1038/nature11701
- 3uon - human muscarinic M2 receptor
- 4daj - rat muscarinic M3 receptor
- 3rze - human histamine H1 receptor
- 2rh1 - human beta-2 adrenergic receptor
- 2vt4 - turkey beta-1 adrenergic receptor
- 3pbl - human dopamine D3 receptor
- 2ydv - human adenosine A2a receptor
- 3v2w - human sphingosine-1-phosphate receptor
- 4djh - human kappa opioid receptor
- 4dkl - mouse mu opioid receptor
- 4ej4 - mouse delta opioid receptor
- 4ea3 - human nociceptin receptor
- 4grv - rat neurotensin receptor
- 3odu - human CXCR4 receptor
- 2lnl - human CXCR1 receptor (NMR)
- 3vw7 - human PAR1 receptor
- 1u19 - bovine rhodopsin
- 2z73 - squid rhodopsin
10 20 30 40 50 60 70 3uon ( 20 ) tfevvfivlvagslSlvTiigNilVmvSIkvnrh 4dajA ( 64 ) iwqvvfiafltgflAlvTiigNilVivAFkvnkq 3rze ( 28 ) mplvvvlsticlvTvglNllVlyAvrserk 2rh1 ( 29 ) devwvvgmgivmslivlaIvfgNvlVitAIakfer 2vt4A ( 40 ) weagmsllmalVvllIvagNvlViaAigstqr 3pblA ( 32 ) yalsYcalilaIvfgNglVcmAVlkera 2ydv ( 3 ) imgssvYitvElaiavlAilgNvlVcwAvwlnsn 3v2w ( 17 ) sdyvnydIIvrHYnyTgklnisa ltsvvfiliCcfIileNifvlltiwktkk 4djhA ( 55 ) spaipviitavysvvfvvGlvgNslVmfVIirytk 4dkl ( 65 ) mvtaitimalYsiVcvvGlfgNflvmyvIvrytk 4ej4 ( 41 ) rsasslalaiaitalYsavcavGllgNvlvmfgIvrytk 4ea3A ( 47 ) plglkvtIvglYlavcvgGllgNclvmyVIlrhtk 4grvA ( 52 ) nsdldVnTdiyskvlvtaiYlalfvvGtvgNsvtlftlark s 3oduA ( 27 ) pçfre-------------------------enanfnkiflptiYsiIfltGivgNglvilvMgyqkk 2lnl ( 29 ) pÇmle--------------------------tetLnkYvviiayalvFllsllgNslvMlvilysrv 3vw7 ( 91 ) dasgYLtsswLtlfVPsvYtgVfvvSlplNimaivvFilkmk 1u19A ( 1 ) mnGtegpnfyVPfsnktgvVrsPFeapQyyLaepwqFsmlAayMflLimlGfpiNflTlyVTvqHkk 2z73A ( 9 ) etwwyNpsIvVhpHWref--------------dqvpdavYyslGifIgiCgiiGcggNgiViyLFtktks aaaaaaaaaaaaaaaaaaaaaaaaaaaa 80 90 100 110 120 130 140 150 3uon ( 54 ) LqtvnnyflfSLAcADliiGvfSMnlytlytvi--gyWplgpvvÇdlWlalDYvVSNAsVmNLliiSfdryfcvt 4dajA ( 98 ) LktvnnyFllSLAcADliIGviSMnlFttyiim--nrWalgnlaÇdlwLSiDYvASNAsVmNLlvISfDryfsit 3rze ( 58 ) LhtvGnlYIvsLSvADliVGavVMpmnilyllm--skwsLgrplÇlfWLSmDYVASTASIfSVfiLCiDryrsvq 2rh1 ( 64 ) LqtvtnyFItsLAcADlvMGlaVVpfgaahilm--kmWtfgnfwçefWTSiDVlCVTASIeTLcvIAvdryfAIt 2vt4A ( 72 ) LqtltnlFItsLAcADlvvGllVVpfgatlvvr--gtWlwgsflçelWTSlDVlCVTAsIeTLcvIAiDrylait 3pblA ( 60 ) LqtttnyLVvsLAvADllvAtlVMpwvvylevt-ggvWnfsricÇdvFVTlDVmMcTAsIwNLCaISidRytAVv 2ydv ( 37 ) LqnvtnyFVvsAAaADilVGvlAIpfaiaIst----GfçaaçhgÇLfiACfVLVLTASSIfSLlaIAiDryiair 3v2w ( 76 ) FhrpMYyFIgnLAlSDllaGvaYtaNlllsga---tTykLtPaqWFlREGsMFvALSASVfSLlaIAieryitml 4djhA ( 90 ) mktaTniYIfNLAlADalVTtTMpfqstvylmn---sWpfgdvlÇkiVlsiDyyNMfTSIfTLtmMSvdRyiaVc 4dkl ( 99 ) MktAtniYIfNLAlADalATsTLpfqsvnylmg---tWpfgnilÇkiviSidYyNMFTSIfTLctMSvdRyiAVC 4ej4 ( 80 ) LktATniYIfNLAlADalATstLpfqsakylme---tWpfgellÇkaVlSidYyNMFTSIfTLtmMSvDRyiavc 4ea3A ( 82 ) mktatNiYIfNLAlADtlVLlTLpfQGtdillg---fWpfgnalÇktVIaiDyyNMFTSTfTLtaMSvdryvaic 4grvA ( 98 ) lqstvhyHlgsLalSDllILllAMpvElyNFIWvhhpWafgdagÇrgyYflRDactYATAlNVasLSvaRylAic 3oduA ( 69 ) lrsmtdkYRlhLSvADllFVitLpfWavDAva----nWyfgnflÇkaVHviYTVNlYSSVwILAfISlDRylAiV 2lnl ( 70 ) GrsvTdvyLlnLalaDllfaltlpiwaaSkvn----gwifgtfLÇkvVslLkEvnfYsgilLlacIsvdrylaiv 3vw7 ( 133 ) vkkPAVVyMlhLAtADvlFVsvLpfkisYyfsg--SdWqfgselÇrfVtAaFYcnMYASIlLMtvISiDrflAVv 1u19A ( 68 ) LrtplNyILlnLAvADlfMVfg-GFtTTlyTSl-hGyFvfgptGÇnlEGffATLGGEIaLWSLvvLaieRyvvVc 2z73A ( 65 ) LqtpanmFiinLAfSDftFSlvNGfplMtiSCf-lkkWifgfaaÇkvYGfiGGiFGFMsIMTMAMiSiDrynViG aaaaaaaaaaaaaaaaaa aaaaaaaaa aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa 160 170 180 190 200 210 220 3uon ( 127 ) kpltypvk---rttkmAgmmiaaAwvlSfilwapaIlfwqfivg-----------vrtVedgeÇyIqff------ 4dajA ( 171 ) rpltyrak---rttkrAgvmiglAwviSfvlWApaIlfwqyfvg-----------krtVppgeÇfIqfl------ 3rze ( 131 ) qplrylky---rtktrAsatilgawflSfl-WvipIlgwnh rredkÇeTdfy------ 2rh1 ( 137 ) spfkyqSl---ltknkArviilmvwivSgltSflpIqmhwyr-----athqeAinÇyae-etçÇdff-------- 2vt4A ( 145 ) spfryqsl---mtrarAkviictvwaiSalvSflpImmhwWr-----dedpqAlkçyqd-pgçÇdfv-------- 3pblA ( 134 ) mpvhyqhgtgqsscrrValmitavwvlAfaVSc-pLlfgfNtTg---------------dptvÇsIs-------- 2ydv ( 108 ) iplryngl---vtgtrAkgiiaicwvlSfaIGltPmlgwnnÇgqp--kegkahsqgÇgegqvAÇlFedVV----- 3v2w ( 148 ) k nnfrlfllisacwviSlilGglPimgwn---------------ÇisalssÇSTVLP------- 4djhA ( 162 ) hpvkaldf---rtplkAkiinicIwllSssvGisAivlGGtkvred------------vdvieÇslqFpdddysw 4dkl ( 171 ) hpvkaldf---rtprnAkivnvcNwilSsaiGlpVmfmAttkyrqg--------------sidçtltfsh-ptwy 4ej4 ( 152 ) hpvkaldf---rtpakAklinicIwvlAsgvGvpimvmAvtqprdg--------------avvÇmlqfps-pswy 4ea3A ( 154 ) hp tsskAqavnvaIwalAsvvGvpvaimGsAqvede--------------eieÇlveipt-pqdy 4grvA ( 173 ) hpfkaktl---msrsrtkkfisaIwlaSallAipMlftMGlqnrSadg--------thpgGlVÇTPiv----dta 3oduA ( 140 ) hatn---sqrprkllAekvVyvgVwipAlllT-ipDfif--Anvsead-----------dryiÇdrfyp---ndl 2lnl ( 141 ) haTr----tltqkrhlvkfvclgcwglsmnlS-lpFflf--RQayhpN----------NsSPvÇyEVlg-ndtak 3vw7 ( 206 ) ypm rtlgrAsftClaiwalAiagV-vpLllkeQtiqvpg-----------lgitTçhdvlsetLleg 1u19A ( 141 ) kpmsn----frfgenhaimgvafTwvmAlaCAapPlvgwSrYIPE-------------GMQCSÇGIDYYTpheet 2z73A ( 139 ) rpmaas---kkMshrrAfimiifVwlwSvlwAigPifgwGaYtLE-------------GVLCNÇSFdYIsr--ds aaaaaaaaaaaaaaaaaaa aaa 230 240 250 260 270 280 290 300 3uon ( 182 ) snaavtfgtAiaaFylpviiMtvlywhisrasksri pppsrekkvtrtilaIllaF 4dajA ( 226 ) septitfgtAiaaFymPvtiMtilywrIyketek like aqTlsaIllaF 3rze ( 186 ) dvtwfkvmtaiinFylPtllMlwfyakIykaVrqhc lhmnrerkaakQLgfIMaaF 2rh1 ( 195 ) TnqayaiasSivSFyvplviMvfvYsrVfqeakrql kfclkeHkaLktlgiIMgtF 2vt4A ( 203 ) TnrayaiasSiiSFyipLliMifvalrvyreakeq irehkalktlgiImgvF 3pblA ( 185 ) -npdFViySSvvSFylPfgvTvlvyarIyvvlkqrrrk-----------------gvplrekkatqMVaiVlgaF 2ydv ( 173 ) pmnYMVyfNffaCVlvPlllMlgvylrIflaarrqlkqmesq stlqkevhaakSLaiIvglF 3v2w ( 197 ) LYhkhYIlfCTtvFtllllsIvilYcriyslvrtr asrssenvaLlkTViiVLsvF 4djhA ( 222 ) wdlfmkicVfifAfviPvliIivcytlMilrlksvrllsg rekdrnlrritrLVlvVVavF 4dkl ( 228 ) wenllKicVfifAfimPvliItvcyglmilrlksvr ekdrnlrritrMVlvVvavF 4ej4 ( 209 ) wdtvtkicvflfAfvvPiliitvcyglMllrlrsvr ekdrslrriTrMVlvVvgaF 4ea3A ( 211 ) wgpvfaiciflfSFivPvlvIsvcyslMirrlrgvrlls-------------gsrekdrnlrritrLVlvVvavF 4grvA ( 233 ) tvkvvIqvNtfmSFlfPmlvIsilNtvIAnkLtvmv vqalrhGVlvAraVviaf 3oduA ( 195 ) wvvvfqfqhimvglilPgivIlsCyciIisklshs kghqkrkalktTviLilaF 2lnl ( 198 ) wrmvLrilPHtfGfivplfvmlfcygftlrtlf---------------------kahmgqkhrAmrvIfaVvlif 3vw7 ( 266 ) yyayyfsafSavfFfvpliiStvCyvsIirclsssa anrskksrAlfLSaaVfcIF 1u19A ( 199 ) nNesFViyMfvvHfiiPlivIffcygqLvftvkeaaaq------------qqesattqkaekevTrMviiMviaF 2z73A ( 196 ) ttrsNIlcMFilGffgPiliiffCyfnIvmsvsnhekemaamakrlnakelrkaqaganaemrlAkIsivIVsqF aaaaaaaaaaa aaaaaaaaaaaaaaaaa aaaaaaaaaaaaaaaa 310 320 330 340 350 360 370 3uon ( 397 ) iitWapYNvmVlintfçap--------ç--ipntvwtiGywlCYinstiNpacYalcnatFkktfkhllm 4dajA ( 500 ) iitWtpyNimVlvntfçds--------ç--ipktywnlgywlCYiNStvNPvcYalcnktFrttfkt 3rze ( 425 ) ilCWipYFiffmviafçkn--------ç--cnehlhmftiWlGYiNStlNPliYplCnenFkktfkrilhi 2rh1 ( 283 ) tlcWlpFFiVNivhviqdn----------lirkevyillNwiGYvNSgfNpliYc-rspdfriAfqellcl 2vt4A ( 300 ) tlCWlpFFlvnivnvfnrd----------lvpdwlfvafnwlGYAnSAmnpiiYc-rspdfrkAfkrlla 3pblA ( 339 ) ivCWlpFFltHvlnthçqt--------ç-hvspelysattwlGYvNsalNPviYttfnieFrkAflkilsc 2ydv ( 243 ) alCWlpLHiiNcftffçpd--------çshaplwlMylAivlSHtNSvvNPfiyAyrireFrqTFrkiirshvlr 3v2w ( 266 ) iacwapLFiLLllDvgçkvk------tç--diLfrAeyfLvlAvlNSgtNPiiytltNkemrrafiri 4djhA ( 284 ) vvcWtpIHifilvealgs aalssyyfcIalGytNSslNPilYafldenFkrcfrdfcfp 4dkl ( 290 ) ivcWtpIHiyViikaliti-------pettfqtvswhfcialGYtNSclNpvlYafldenFkrCfrefci 4ej4 ( 271 ) vvCWapIHifVivwtlvdi------nrrdplvvaalhlcialGYaNSslNpvlYaflDenfkrc 4ea3A ( 273 ) vgcWtpVQvfvlaqglgvq-------pssetavailrfctAlGYvNSclNpilYafldenFkacfr 4grvA ( 318 ) vvcWlpYHvRRlmFCyisdeq--WttflFdfYHyfYmlTNalAYasSAinpilYnlvsanFrqv 3oduA ( 249 ) facWlpyyigisidsfilleiikqgçefentvhkwisitEAlAFfHCclNpilyaflgakfktsaqhalts 2lnl ( 252 ) llcwlpynlvlLadTlmrtqviqesçeRrNnIGraLdatEilGflhsclnpiiyafigqnfrhgflkilamhg 3vw7 ( 323 ) iiCFgpTNvlLiaHYsflsh-----tstteaAYfaYLlcvCvSSiSCciDplIyyyAssec 1u19A ( 262 ) liCWlpYAgvAfyIfthqgsd---------fgpifMTipAFfAKtSAvyNPviYimmnkqFrnCmvttlccgknp 2z73A ( 271 ) llSWspYAvvAllAQfgplew---------VtpyaAQlpVMfAKaSaihNPmiYsvsHpkFreAIsqtfpwvLtc aaaaaaaaaaaaaaaa aaaaaaaaaaaaa aaaaaaaa aaaaaaaa 380 390 400 410 3uon 4dajA 3rze 2rh1 2vt4A 3pblA 2ydv ( 310 ) qqepfkaa 3v2w 4djhA 4dkl 4ej4 4ea3A 4grvA 3oduA 2lnl 3vw7 1u19A ( 328 ) lgddeasttVsktetsqvapa 2z73A ( 337 ) cqfddketeddkdaeteipage