GPCR Structures: mu and kappa opioid structures
So, two more GPCR structures in last weeks Nature magazine. This time two paralogous opioid receptors, the mu (human UniProt:P35372) and kappa (human UniProt:P41145) subtypes, one from mouse, the other from human, and both complexed to synthetic antagonists. These continue to add to our ability to understand and predict pharmacology of known and future drugs, but also will be great examples for engagement with the public over science - everyone has heard of opiates, and heroin and morphine, even my kids have!
%A A. Manglik %A A. Kruse %A T. Kobilka %A F. Thian %A J. Mathiesen %A R. Sunahara %A L. Pardo %A W. Weis %A B. Kobilka %A S. Granier %D 2012 %T Crystal structure of the µ-opioid receptor bound to a morphinan antagonist %J Nature %O DOI: 10.1038/nature10954 %A H. Wu %A D. Wacker %A M. Mileni %A V. Katritch %A G. Han %A E. Varmy %A W. Liu %A A. Thompson %A X. Huang %A F. Carroll %A S. Mascarella %A R. Westkaemper %A P. Mosier %A B. Roth %A V. Cherezov %A R. Stevens, R. %D 2012 %T Structure of the human κ-opioid receptor in complex with JDTic %J Nature %O DOI: 10.1038/nature10939
Here's an alignment for the 13 sequence distinct structures; I don't think it's completely right in several places, but it is a challenging family to align completely and certainly it's not unambiguous, but it's a start.
- 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
- 3odu - human CCR4 receptor
- 2i35 - bovine rhodopsin
- 2z73 - squid rhodopsin
10 20 30 40 50 3uon ( 20 ) tfevvfivl 4dajA ( 64 ) iwqvvfiaf 3rze ( 28 ) mplvv 2rh1 ( 29 ) devwvvgmgi 2vt4A ( 40 ) weagmsl 3pblA ( 32 ) yal 2ydv ( 3 ) imgssvYit 3v2w ( 17 ) sdyvnydIIvrHYnyTgklnisa ltsv 4djhA ( 55 ) spaipviita 4dkl ( 65 ) mvtaitima 3oduA ( 27 ) pçfre-------------------------enanfnkiflpt 1u19A ( 1 ) mnGtegpnfyVPfsnktgvVrsPFeapQyyLaepwqFsmlAa 2z73A ( 9 ) etwwyNpsIvVhpHWref--------------dqvpdavYyslGi aaaaa 60 70 80 90 100 3uon ( 29 ) vagslSlvTiigNilVmvSIkvnrhLqtvnnyflfSLAcADliiGvfSMn 4dajA ( 73 ) ltgflAlvTiigNilVivAFkvnkqLktvnnyFllSLAcADliIGviSMn 3rze ( 33 ) vlsticlvTvglNllVlyAvrserkLhtvGnlYIvsLSvADliVGavVMp 2rh1 ( 39 ) vmslivlaIvfgNvlVitAIakferLqtvtnyFItsLAcADlvMGlaVVp 2vt4A ( 47 ) lmalVvllIvagNvlViaAigstqrLqtltnlFItsLAcADlvvGllVVp 3pblA ( 35 ) sYcalilaIvfgNglVcmAVlkeraLqtttnyLVvsLAvADllvAtlVMp 2ydv ( 12 ) vElaiavlAilgNvlVcwAvwlnsnLqnvtnyFVvsAAaADilVGvlAIp 3v2w ( 51 ) vfiliCcfIileNifvlltiwktkkFhrpMYyFIgnLAlSDllaGvaYta 4djhA ( 65 ) vysvvfvvGlvgNslVmfVIirytkmktaTniYIfNLAlADalVTtTMpf 4dkl ( 74 ) lYsiVcvvGlfgNflvmyvIvrytkMktAtniYIfNLAlADalATsTLpf 3oduA ( 44 ) iYsiIfltGivgNglvilvMgyqkklrsmtdkYRlhLSvADllFVitLpf 1u19A ( 43 ) yMflLimlGfpiNflTlyVTvqHkkLrtplNyILlnLAvADlfMVfg-GF 2z73A ( 40 ) fIgiCgiiGcggNgiViyLFtktksLqtpanmFiinLAfSDftFSlvNGf aaaaaaaaaaaaaaaaaaaaaa aaaaaaaaaaaaaaaaaa aaa 110 120 130 140 150 3uon ( 79 ) lytlytvi-gyWplgpvvÇdlWlalDYvVSNAsVmNLliiSfdryfcvtk 4dajA ( 123 ) lFttyiim-nrWalgnlaÇdlwLSiDYvASNAsVmNLlvISfDryfsitr 3rze ( 83 ) mnilyllm-skwsLgrplÇlfWLSmDYVASTASIfSVfiLCiDryrsvqq 2rh1 ( 89 ) fgaahilm-kmWtfgnfwçefWTSiDVlCVTASIeTLcvIAvdryfAIts 2vt4A ( 97 ) fgatlvvr-gtWlwgsflçelWTSlDVlCVTAsIeTLcvIAiDrylaits 3pblA ( 85 ) wvvylevtggvWnfsricÇdvFVTlDVmMcTAsIwNLCaISidRytAVvm 2ydv ( 62 ) faiaIst---GfçaaçhgÇLfiACfVLVLTASSIfSLlaIAiDryiairi 3v2w ( 101 ) Nlllsga--tTykLtPaqWFlREGsMFvALSASVfSLlaIAieryitmlk 4djhA ( 115 ) qstvylmn--sWpfgdvlÇkiVlsiDyyNMfTSIfTLtmMSvdRyiaVch 4dkl ( 124 ) qsvnylmg--tWpfgnilÇkiviSidYyNMFTSIfTLctMSvdRyiAVCh 3oduA ( 94 ) WavDAva---nWyfgnflÇkaVHviYTVNlYSSVwILAfISlDRylAiVh 1u19A ( 92 ) tTTlyTSlhGyFvfgptGÇnlEGffATLGGEIaLWSLvvLaieRyvvVck 2z73A ( 90 ) plMtiSCflkkWifgfaaÇkvYGfiGGiFGFMsIMTMAMiSiDrynViGr aaaaaaa aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa 160 170 180 190 200 3uon ( 128 ) pltypvk---rttkmAgmmiaaAwvlSfilwapaIlfwqfivg------- 4dajA ( 172 ) pltyrak---rttkrAgvmiglAwviSfvlWApaIlfwqyfvg------- 3rze ( 132 ) plrylky---rtktrAsatilgawflSfl-WvipIlgwnh 2rh1 ( 138 ) pfkyqSl---ltknkArviilmvwivSgltSflpIqmhwyr-----athq 2vt4A ( 146 ) pfryqsl---mtrarAkviictvwaiSalvSflpImmhwWr-----dedp 3pblA ( 135 ) pvhyqhgtgqsscrrValmitavwvlAfaVSc-pLlfgfNtTg------- 2ydv ( 109 ) plryngl---vtgtrAkgiiaicwvlSfaIGltPmlgwnnÇgqp--kegk 3v2w ( 156 ) nnfrlfllisacwviSlilGglPimgwn----------- 4djhA ( 163 ) pvkaldf---rtplkAkiinicIwllSssvGisAivlGGtkvred----- 4dkl ( 172 ) pvkaldf---rtprnAkivnvcNwilSsaiGlpVmfmAttkyrqg----- 3oduA ( 141 ) atn----sqrprkllAekvVyvgVwipAlllT-ipDfif-Anvsead--- 1u19A ( 142 ) pmsn----frfgenhaimgvafTwvmAlaCAapPlvgwSrYIPE------ 2z73A ( 140 ) pmaas---kkMshrrAfimiifVwlwSvlwAigPifgwGaYtLE------ aaaaaaaaaaaaaaaaaaa 210 220 230 240 250 3uon ( 168 ) ----vrtVedgeÇyIqff------snaavtfgtAiaaFylpviiMtvlyw 4dajA ( 212 ) ----krtVppgeÇfIqfl------septitfgtAiaaFymPvtiMtilyw 3rze ( 175 ) rredkÇeTdfy------dvtwfkvmtaiinFylPtllMlwfya 2rh1 ( 180 ) eAinÇyae-etçÇdff--------TnqayaiasSivSFyvplviMvfvYs 2vt4A ( 188 ) qAlkçyqd-pgçÇdfv--------TnrayaiasSiiSFyipLliMifval 3pblA ( 177 ) --------dptvÇsIs---------npdFViySSvvSFylPfgvTvlvya 2ydv ( 154 ) ahsqgÇgegqvAÇlFedVV-----pmnYMVyfNffaCVlvPlllMlgvyl 3v2w ( 184 ) ----ÇisalssÇSTVLP-------LYhkhYIlfCTtvFtllllsIvilYc 4djhA ( 205 ) -------vdvieÇslqFpdddyswwdlfmkicVfifAfviPvliIivcyt 4dkl ( 214 ) ---------sidçtltfsh-ptwywenllKicVfifAfimPvliItvcyg 3oduA ( 182 ) --------dryiÇdrfyp---ndlwvvvfqfqhimvglilPgivIlsCyc 1u19A ( 182 ) -------GMQCSÇGIDYYTpheetnNesFViyMfvvHfiiPlivIffcyg 2z73A ( 181 ) -------GVLCNÇSFdYIsr--dsttrsNIlcMFilGffgPiliiffCyf aaaaaaaaaa aaaaaaaaaaaa 260 270 280 290 300 3uon ( 208 ) hisrasksri pppsrekkvtrtilaIllaFi 4dajA ( 252 ) rIyketek like aqTlsaIllaFi 3rze ( 212 ) kIykaVrqhc lhmnrerkaakQLgfIMaaFi 2rh1 ( 221 ) rVfqeakrql kfclkeHkaLktlgiIMgtFt 2vt4A ( 229 ) rvyreakeq irehkalktlgiImgvFt 3pblA ( 210 ) rIyvvlkqrrrk-----------------gvplrekkatqMVaiVlgaFi 2ydv ( 199 ) rIflaarrqlkqmesq stlqkevhaakSLaiIvglFa 3v2w ( 223 ) riyslvrtr asrssenvaLlkTViiVLsvFi 4djhA ( 248 ) lMilrlksvrllsg rekdrnlrritrLVlvVVavFv 4dkl ( 254 ) lmilrlksvr ekdrnlrritrMVlvVvavFi 3oduA ( 221 ) iIisklshs kghqkrkalktTviLilaFf 1u19A ( 225 ) qLvftvkeaaaq------------qqesattqkaekevTrMviiMviaFl 2z73A ( 222 ) nIvmsvsnhekemaamakrlnakelrkaqaganaemrlAkIsivIVsqFl aaaaa aaaaaaaaaaaaaaaaa 310 320 330 340 350 3uon ( 398 ) itWapYNvmVlintfçap--------ç--ipntvwtiGywlCYinstiNp 4dajA ( 501 ) itWtpyNimVlvntfçds--------ç--ipktywnlgywlCYiNStvNP 3rze ( 426 ) lCWipYFiffmviafçkn--------ç--cnehlhmftiWlGYiNStlNP 2rh1 ( 284 ) lcWlpFFiVNivhviqdn----------lirkevyillNwiGYvNSgfNp 2vt4A ( 301 ) lCWlpFFlvnivnvfnrd----------lvpdwlfvafnwlGYAnSAmnp 3pblA ( 340 ) vCWlpFFltHvlnthçqt--------ç-hvspelysattwlGYvNsalNP 2ydv ( 244 ) lCWlpLHiiNcftffçpd--------çshaplwlMylAivlSHtNSvvNP 3v2w ( 267 ) acwapLFiLLllDvgçkvk------tç--diLfrAeyfLvlAvlNSgtNP 4djhA ( 285 ) vcWtpIHifilvealgs aalssyyfcIalGytNSslNP 4dkl ( 291 ) vcWtpIHiyViikaliti-------pettfqtvswhfcialGYtNSclNp 3oduA ( 250 ) acWlpyyigisidsfilleiikqgçefentvhkwisitEAlAFfHCclNp 1u19A ( 263 ) iCWlpYAgvAfyIfthqgsd---------fgpifMTipAFfAKtSAvyNP 2z73A ( 272 ) lSWspYAvvAllAQfgplew---------VtpyaAQlpVMfAKaSaihNP aaaaaaaaaaaaaaa aaaaaaaaaaaaa aaa 360 370 380 390 400 3uon ( 438 ) acYalcnatFkktfkhllm 4dajA ( 541 ) vcYalcnktFrttfkt 3rze ( 466 ) liYplCnenFkktfkrilhi 2rh1 ( 324 ) liYc-rspdfriAfqellcl 2vt4A ( 341 ) iiYc-rspdfrkAfkrlla 3pblA ( 381 ) viYttfnieFrkAflkilsc 2ydv ( 286 ) fiyAyrireFrqTFrkiirshvlrqqepfkaa 3v2w ( 309 ) iiytltNkemrrafiri 4djhA ( 328 ) ilYafldenFkrcfrdfcfp 4dkl ( 334 ) vlYafldenFkrCfrefci 3oduA ( 300 ) ilyaflgakfktsaqhalts 1u19A ( 304 ) viYimmnkqFrnCmvttlccgknplgddeasttVsktetsqvapa 2z73A ( 313 ) miYsvsHpkFreAIsqtfpwvLtccqfddketeddkdaeteipage aaaaa aaaaaaaaaa 410