ChEMBL

Since the last GPCR structure post of jpo, three novel GPCR receptors have had their structure solved.

1) 5-hydroxytryptamine receptor 1B, 5-HT1B, in complex with the agonist Ergotamine(4iaq) (1)
2) 5-hydroxytryptamine receptor 1B, 5-HT2B, in complex with Dihydroergotamine and Ergotamine (4ib4, 4iar) (1)
3) The first class F receptor, the Smoothed Homolog (2), in complex with an agonizing anti-tumor agent, LY2940680 (4jkv)

The latter gave me quite a headache since its sequence identify with class A GPCRs is <10, and it is missing some of the very conserved motifs. Trying to align it with pure sequence alignment is next to impossible. Luckely I could make use of 3D-Coffee, heavily overweighting the pairwise structural alignment produced by TMalign and sap. Mind you, the alignment could probably be optimized manually, but it is quite encouraging to see an automated mechanism doing such a good job. Oh, did I mention, you'll be able to inspect all of these alignments yourself in the upcoming version of the GPCR SARfari?

1. 4iaq (red) - Human 5-hydroxytryptamine receptor 1B
2. 4ib4A (red) - Human 5-hydroxytryptamine receptor 2B
3. 4jkvA (orange) - Human Smoothened Homolog
4. 3vw7 (pink) - Human Proteinase-activated receptor 1
5. 1f88A (yellow) - Bos taurus Rhodopsin
6. 2rh1 (green) - Human Beta-2 adrenergic receptor
7. 4djhA (violet) - Human Kappa-type opioid receptor
8. 4ej4 (blue) - Mus musculus Delta-type opioid receptor


Despite being so structurally different, there is a good conservation in the 3D structure - See figure 1. The superimposing was done using mnyfit, a program jpo wrote (3) sometime back when he was still a young lad pursuing a PhD degree. Oh, and a(nother) small teaser, that screenshot comes from the updated version of the GPCR SARfari I'm working on, where you can interact with the superimposed structures, showing ligands, binding sites etc.


It seems the next major one will be the first class B, the Glucagon receptor. Hopefully this won't break my code and set back my work a few weeks.

10        20        30        40        50  
4iaq   (  38 )                              y-iyQdsislpwkvllvmllal-i
4lb4A  (  48 )                                  ee-q-gnkl-hwAallilmv
4jkvA  ( 190 )    sgqÇevPLvrTdnpkSwyedveGÇGI-qçqNpLFteaeHqdMhsyIaa-f
3vw7   (  91 )                               dasgYLtsswLtlfVPsvYtg-V
1f88A  (   1 )     mnGtegpnfyVPfsnktgvVrsPfea-pQyyLaepwqFsmlAayMfl-l
2rh1   (  29 )                                      devwvvgmgivmsl-i
4djhA  (  55 )                                      spaipviitavysv-v
4ej4   (  41 )                                  rsasslalaiaitalYsa-v
                                                      aaaaaaaaaaaa a

                           60        70        80        90        100 
4iaq   (  60 )    tlaTtlsNafViatVyrt-rkLhtpanyLiasLAvTDllVSilVMpi---
4lb4A  (  65 )    iipTigGNtlVilAVsle-kkLqyatnyFlmsLAvADllVGlfVMpi---
4jkvA  ( 238 )    GavTglcTlfTlaTFvadwrnsnrypaVILfyVNaCffvgSiGWlaQfmd
3vw7   ( 113 )    fvvSlplNimaivvFilk-mkvkkPAVVyMlhLAtADvlFVsv-Lpf---
1f88A  (  48 )    imlGfpiNflTlyVTvqH-kkLrtpLNyILlnLAvADlfMVfgGFtT---
2rh1   (  44 )    vlaIvfgNvlVitAIakf-erLqtvtnyFItsLAcADlvMGlaVVpf---
4djhA  (  70 )    fvvGlvgNslVmfVIiry-tkmktaTniYIfNLAlADalVTtT-Mpf---
4ej4   (  60 )    cavGllgNvlvmfgIvry-tkLktATniYIfNLAlADalATst-Lpf---
                  aaaaaaaaaaaaaaaaa       aaaaaaaaaaaaaaaaaa  aaa   

                           110       120       130       140       150 
4iaq   ( 106 )    ----------Stmytv-tg-rWtlgqvvÇdfWlssDItCCTASIwHLCvi
4lb4A  ( 111 )    ----------aLltim-feamWplplvlÇpawLflDVlfSTASIwHLCaI
4jkvA  ( 288 )    garreIVçRadgTMRl-gE-pTsnetlsÇviiFviVYyAlMAGvvWFvvL
3vw7   ( 158 )    ----------kisYyfsgS-dWqfgselÇrfVtAaFYcnMYASIlLMtvI
1f88A  (  94 )    ----------TlyTSl-hG-yFvfgptGÇnlEGffATLGGEIaLwSLvvL
2rh1   (  90 )    ----------gaahil-mk-mWtfgnfwçefWTSiDVlCVTASIeTLcvI
4djhA  ( 115 )    ----------qstvyl-mn-sWpfgdvlÇkiVlsiDyyNMfTSIfTLtmM
4ej4   ( 105 )    ----------qsakyl-me-tWpfgellÇkaVlSidYyNMFTSIfTLtmM
                            aaaaaa         aaaaaaaaaaaaaaaaaaaaaaaaa

                           160       170       180       190       200 
4iaq   ( 144 )    AldrywaitdaveysakrtpkraavmialvwvfSisISl-pPf-fw-r--
4lb4A  ( 150 )    svdryiaIkkpiqanqynsratAfikitvVwliSigiAi-pVpikg-i--
4jkvA  ( 336 )    TyAWHTsFkalgttyqpgk-t--syfhllTwslPfvlTv-aIlavaqVDG
3vw7   ( 197 )    SiDrflAVvypm-----rtlgrAsftClaiwalAiagVv-pLllke-Qti
1f88A  ( 132 )    aieRyvvvckpmsn-frfgenhAimgvafTwvmAlaCAa-pPlvgwSr--
2rh1   ( 128 )    AvdryfAItspfkyqSlltknkArviilmvwivSgltSflpIqmhwyr-a
4djhA  ( 153 )    SvdRyiaVchpvkaldfrtplkAkiinicIwllSssvGi-sAivlG-Gtk
4ej4   ( 143 )    SvDRyiavchpvkaldfrtpakAklinicIwvlAsgvGv-pimvmA-vtq
                  aaaaaaaaa          aaaaaaaaaaaaaaaaaaa  aaa       

                           210       220       230       240       250 
4iaq   ( 189 )    ------qa------s-eÇvv---n--------tdhilytvySTvgAFyfP
4lb4A  ( 196 )    ------et-np-nni-tÇvL---t-------kerFgdfMlfgSlaAFftP
4jkvA  ( 384 )    -DsV---------SG-IÇF-----------VGYknyryRagfVlapIglV
3vw7   ( 245 )    qvpglg-------it-Tçhdvlset----LlegyyayyfsafSavfFfvp
1f88A  ( 178 )    ------YI-PE-GMQCSÇGI---DY-YTpheetnNesFViyMfvvHfiiP
2rh1   ( 177 )    -thqe-AinÇyaeet-çÇdf---f---------TnqayaiasSivSFyvp
4djhA  ( 201 )    vredv-------dvi-eÇsl---qFpd-ddyswwdlfmkicVfifAfviP
4ej4   ( 191 )    prdg---------av-vÇml---qf-p-spswywdtvtkicvflfAfvvP
                                                     aaaaaaaaaa  aaa

                           260       270       280       290       300 
4iaq   ( 221 )    tllLialygrIyvears--r--------------ilma----arerkaTk
4lb4A  ( 230 )    laiMivtyfltihALqkk---a---------------q--tisneqrask
4jkvA  ( 412 )    livGgyfLirGvmtlfsIksn----hpglLsekaa---skinetMlrLgi
3vw7   ( 283 )    liiStvCyvsIirclss--s-a------------------anrskksrAl
1f88A  ( 216 )    livIffcygqLvftvkea---AaS-------------a-ttqkaekevTr
2rh1   ( 212 )    lviMvfvYsrVfqeakr--q--------------l--k--fclkeHkaLk
4djhA  ( 239 )    vliIivcytlMilrlksv---r-lls--------g---rekdrnlrritr
4ej4   ( 226 )    iliitvcyglMllrlrsv---r-----------------ekdrslrriTr
                  aaaaaaaaaaaaaa                             aaaaaaa

                           310       320       330       340       350 
4iaq   ( 315 )    tLgiIlgaF-ivCWlpFFiiSlvmpi------------------------
4lb4A  ( 325 )    vlgivFflF-llmWcpFFitNitLvl-çd--sç---------------nq
4jkvA  ( 455 )    fGflAfgfv-liTfscHfyDffnQae-We--rSFrdyVlçqançeiknr-
3vw7   ( 313 )    fLSaaVfcIFiiCFgpTNvlLiaHYsfl-sht-------------st--t
1f88A  ( 253 )    MViiMviaF-liCWlpYAgvAfyIft-hq--gs---------------d-
2rh1   ( 274 )    tlgiIMgtF-tlcWlpFFiVNivhvi-qd---n---------------l-
4djhA  ( 275 )    LVlvVVavF-vvcWtpIHifilveal-gs---------------------
4ej4   ( 262 )    MVlvVvgaF-vvCWapIHifVivwtl-vd--in-----------rrd-p-
                  aaaaaaaaa aaaaaaaaaaaaaaaa                        

                           360       370       380       390       400 
4iaq   ( 347 )    --hlaifdffTwlGYlNSliNPiiYtmsnedFkqafhkli-rfk      
4lb4A  ( 356 )    ttlqmlLeifvWiGYvSSGvNPlvyTlfnktFrdAfgrYi-tcnyr    
4jkvA  ( 513 )    -PsllvEkiNLfAmFgtGiaMStwvwtkatlliwrr-------twc    
3vw7   ( 347 )    eaAYfaYLlcvCvSSiSCciDplIyyyAssec                  
1f88A  ( 283 )    -fgPifMtipAFfAKtSAvyNPviYimmnkqFrnCmvttl-ccgknpstt
2rh1   ( 303 )    -irkevyillNwiGYvNSgfNpliYc-rspdfriAfqell-c--------
4djhA  ( 307 )    -aalssyyfcIalGytNSslNPilYafldenFkrcfrdfcf--p      
4ej4   ( 295 )    -lvvaalhlcialGYaNSslNpvlYaflDenfkrc               
                     aaaaaaaaaaaaaaaaaaaaaaa   aaaaaaa              

                           410 
4iaq                          
4lb4A                         
4jkvA                         
3vw7                          
1f88A  ( 337 )    vsktetsqvapa
2rh1   ( 342 )    ------l     
4djhA                         
4ej4                          
                              

(1) Chong Wang et al., Science 3 May 2013: 340 (6132), 610-614
(2) Chong Wang et al., Nature 16 May 2013: 497, 338–343
(3) Kenji Mizuguch et al., Protein Science Nov 1998: 7 (11), 2469-2471


Updated: Somehow the HTML didn't render properly.