It's that time again.. An update on the GPCR structures!
It's been roughly a month ago since the last update on GPCR structures, and, oh boy, we do live in interesting times!
As I mentioned in my last post, the next major publication would probably be the glucagon receptor. And indeed it was (4L6R, 1). However, the good folks at Heptares had a surprise for us, as they simultaneous released the structure of the corticotropin-releasing factor receptor 1 (4K5Y, 2). Two class B GPCRs in just one month!
Despite the glucagon structure only having a resolution of 3.3Å, it does show some interesting features. The binding pocket of the protein is exceptionally large, which is not surprising when considering its main ligand, glucagon. Also, the N-terminus of the first transmembrane helix is a bit longer than in any solved class A structures. This protein has been recognised as a potential drug target for diabetes-2, and this solved structure can hopefully help in this process. The protein was crystallized in complex with the antagonist NNC0640 (Sorry, no ChEMBL entry just yet!), however, it could not be reliably identified by electron density, so sadly the binding mode could not be identified.
The corticotropin-releasing factor receptor is an interesting target, in the sense that it is already a well established drug target for diseases like diabetes, depression etc. The receptor was crystallized in a complex with the antagonist CP-376395
The GPCR structure research has also entered what I'd like to call phase 2. The first GPCRs with a disease-causing mutation was actually released a few months ago, but I missed them! 4BEZ and 4BEY both feature a G90D mutation in rhodopsin which causes night blindess (3). It'll be interesting to see when these starts being as common as mutated kinases!
Ah, and as I ranted about in my last post, alignment based on pure sequence alone is next to impossible. Luckily, GPCRs share the common fold of having 7 transmembrane helices, so a 3D based pairwise alignment works out quite well! See first figure for the MNYFIT 'referenceless' structural alignment. The sequence alignment produced using t_coffee with Joy markup is displayed at the buttom.
1. 4grvA (turquise) - Rat neurotensin receptor NTS1
2. 4l6rA (light purple) - Human Glucagon receptor
3. 1f88A (yellow) - Bovine Rhodopsin
4. 4k5yA (red) - Human corticotropin-releasing factor receptor
(1) Siu, F.Y et al., Nature 16 Juli 2013: 499, 444–9
(2) Hollenstein, K et al., Nature 16 Juli 2013: Advance Online Publication, 1476-4687
(3) Singhal, A et al., EMBO Rep, June 2013, 14(6):520-6
david
As I mentioned in my last post, the next major publication would probably be the glucagon receptor. And indeed it was (4L6R, 1). However, the good folks at Heptares had a surprise for us, as they simultaneous released the structure of the corticotropin-releasing factor receptor 1 (4K5Y, 2). Two class B GPCRs in just one month!
Despite the glucagon structure only having a resolution of 3.3Å, it does show some interesting features. The binding pocket of the protein is exceptionally large, which is not surprising when considering its main ligand, glucagon. Also, the N-terminus of the first transmembrane helix is a bit longer than in any solved class A structures. This protein has been recognised as a potential drug target for diabetes-2, and this solved structure can hopefully help in this process. The protein was crystallized in complex with the antagonist NNC0640 (Sorry, no ChEMBL entry just yet!), however, it could not be reliably identified by electron density, so sadly the binding mode could not be identified.
The corticotropin-releasing factor receptor is an interesting target, in the sense that it is already a well established drug target for diseases like diabetes, depression etc. The receptor was crystallized in a complex with the antagonist CP-376395
The GPCR structure research has also entered what I'd like to call phase 2. The first GPCRs with a disease-causing mutation was actually released a few months ago, but I missed them! 4BEZ and 4BEY both feature a G90D mutation in rhodopsin which causes night blindess (3). It'll be interesting to see when these starts being as common as mutated kinases!
Ah, and as I ranted about in my last post, alignment based on pure sequence alone is next to impossible. Luckily, GPCRs share the common fold of having 7 transmembrane helices, so a 3D based pairwise alignment works out quite well! See first figure for the MNYFIT 'referenceless' structural alignment. The sequence alignment produced using t_coffee with Joy markup is displayed at the buttom.
1. 4grvA (turquise) - Rat neurotensin receptor NTS1
2. 4l6rA (light purple) - Human Glucagon receptor
3. 1f88A (yellow) - Bovine Rhodopsin
4. 4k5yA (red) - Human corticotropin-releasing factor receptor
10 20 30 40 50 4grvA ( 52 ) nsdldVnTdiyskvlvtaiYlalfvv 4l6rA ( 123 ) mdgeeievqkevakmyssfqvmytvGYsl 1f88A ( 1 ) mnGtegpnfyVPfsnktgvVrsPfeapQyyLaepwqFsmlAayMflliml 4k5yA ( 115 ) hyhvaaiinylGhci aaaaaaaaaaaaaaaaa 60 70 80 90 100 4grvA ( 78 ) GtvgNsvtlftlar-k--slqstvhyHlgsLalSDllILllAMpvElyNF 4l6rA ( 152 ) SlgaLllAlaiLggl--sklhctrNaIHanLFaSFvlkAssv-lvidgl- 1f88A ( 51 ) GfpiNflTlyVTvqHk--kLrtpLNyILlnLAvADlfMVfgGFtTTlyT- 4k5yA ( 130 ) SlvaLlvAfvlFlr--arsircLrNiIHanLIaAFilrnatw-fvvqlT- aaaaaaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaa 110 120 130 140 150 4grvA ( 129 ) IwvhhpWafgdagÇrgyYflRDactYATAlNVasLSvaRylAichpfkak 4l6rA ( 198 ) lrt--lsdgavagÇrvaavfmqyGiVaNYcWLlVEglyLhnllglatl-- 1f88A ( 98 ) Slh-GyFvfgptGÇnlEGffATLGGEIaLwSLvvLaieRyvvvckpms-n 4k5yA ( 176 ) msp-evhqsnvgwÇrlvtaaynyfhVTNFFWMfGeGcylhtaIvl----- aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa 160 170 180 190 200 4grvA ( 179 ) tlmsrsrtkkfisaIwlaSallAi-pMlftMGlqnrSad-gthpgGlVÇT 4l6rA ( 259 ) p--ersffslylgigwgaPmlfVvpwavvkclf------en-v----qçw 1f88A ( 146 ) frfgenhAimgvafTwvmAlaCAa-pPlvgwSrYIPEGM------QCSÇG 4k5yA ( 220 ) t--drlrawmficiGwgvPfpiivaWaigKlyy------dn-e----kÇw aaaaaaa aaaaaa aaaa 210 220 230 240 250 4grvA ( 227 ) ----PivdtatvkvvIqvNtfmSFlfPmlvIsilNtvIAnkLtvmv---- 4l6rA ( 296 ) t-------s-ndnmgfwwilrfPvflailiNffifvrIvqllvaklra-- 1f88A ( 189 ) IDYYTpheetnNesFViyMfvvHfiiPlivIffcygqLvftvkeaA--aS 4k5yA ( 260 ) aG------krpgvyTdyiyqgp-MalvlliNfiflfnIvrilmtklra-- aaaaaaaaa aaaaaaaaaaaaaaaaaa 260 270 280 290 300 4grvA ( 300 ) ---v------qalrhGVlvAraVviafvvcWlpYHvRRlmFCyisdeqWt 4l6rA ( 336 ) ----rqmhhtdykfrlAksTltLIplLGvhevvfafvt-d-ehaq----- 1f88A ( 241 ) attq------kaekevTrMViiMviaFliCWlpYAgvAfyIfthq--g-- 4k5yA ( 301 ) ----sttseTiqArkavkaTlvLlplLgitymlafvnevs---------- aaaaaaaaa aaaaaaaaaaaaaa aa 310 320 330 340 350 4grvA ( 341 ) tflFdfYHyfYmlTNalAYasSAinpilYnlvsanFrqv 4l6rA ( 375 ) ---gtlrsaklffdlflsSfqGllVAvlYCflnkeVqselrrrwhrwrlg 1f88A ( 281 ) ---sdfgPifMtipAFfAKtSAvyNPviYimmnkqFrnCmvttlccgknp 4k5yA ( 341 ) ------rvvfiyfnAfLeSfqGffVSvfAcflns aaaaaaaaaaaaa aaaaaaaaaaaa 360 4grvA 4l6rA ( 422 ) kvlweern 1f88A ( 334 ) sttvsktetsqvapa 4k5yANature. 2013 Jul 25;499(7459):444-9
(1) Siu, F.Y et al., Nature 16 Juli 2013: 499, 444–9
(2) Hollenstein, K et al., Nature 16 Juli 2013: Advance Online Publication, 1476-4687
(3) Singhal, A et al., EMBO Rep, June 2013, 14(6):520-6
david