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- EMDB-30936: Molecular insights into ago-allosteric modulation of the human gl... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-30936 | |||||||||
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Title | Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor | |||||||||
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Function / homology | ![]() glucagon-like peptide 1 receptor activity / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / glucagon receptor activity / hormone secretion / Activation of the phototransduction cascade / positive regulation of blood pressure / post-translational protein targeting to membrane, translocation / Activation of G protein gated Potassium channels ...glucagon-like peptide 1 receptor activity / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / glucagon receptor activity / hormone secretion / Activation of the phototransduction cascade / positive regulation of blood pressure / post-translational protein targeting to membrane, translocation / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / G alpha (q) signalling events / response to psychosocial stress / G alpha (i) signalling events / regulation of heart contraction / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / peptide hormone binding / activation of adenylate cyclase activity / negative regulation of blood pressure / cAMP-mediated signaling / adenylate cyclase-activating G protein-coupled receptor signaling pathway / photoreceptor disc membrane / Glucagon-type ligand receptors / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / transmembrane signaling receptor activity / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / positive regulation of cytosolic calcium ion concentration / G alpha (s) signalling events / learning or memory / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / membrane / plasma membrane / cytoplasm Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.9 Å | |||||||||
![]() | Cong ZT / Chen LN / Ma HL / Zhou QT / Yang DH / Xu HE / Zhang Y / Wang MW | |||||||||
![]() | ![]() Title: Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor. Authors: Zhaotong Cong / Li-Nan Chen / Honglei Ma / Qingtong Zhou / Xinyu Zou / Chenyu Ye / Antao Dai / Qing Liu / Wei Huang / Xianqiang Sun / Xi Wang / Peiyu Xu / Lihua Zhao / Tian Xia / Wenge Zhong ...Authors: Zhaotong Cong / Li-Nan Chen / Honglei Ma / Qingtong Zhou / Xinyu Zou / Chenyu Ye / Antao Dai / Qing Liu / Wei Huang / Xianqiang Sun / Xi Wang / Peiyu Xu / Lihua Zhao / Tian Xia / Wenge Zhong / Dehua Yang / H Eric Xu / Yan Zhang / Ming-Wei Wang / ![]() Abstract: The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy ...The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric G. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics. | |||||||||
History |
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Structure visualization
Movie |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 28.6 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 13 KB 13 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 7.2 KB | Display | ![]() |
Images | ![]() | 22.5 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7e14MC ![]() 7duqC ![]() 7durC ![]() 7evmC M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 1.045 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
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Sample components
-Entire : compound2_GLP1R_OWL833_Gs-complex
Entire | Name: compound2_GLP1R_OWL833_Gs-complex |
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Components |
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-Supramolecule #1: compound2_GLP1R_OWL833_Gs-complex
Supramolecule | Name: compound2_GLP1R_OWL833_Gs-complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: ![]() |
Recombinant expression | Organism: Insect cell expression vector pTIE1 (others) |
-Macromolecule #1: compound2_GLP1R_OWL833_Gs-complex
Macromolecule | Name: compound2_GLP1R_OWL833_Gs-complex / type: other / ID: 1 / Classification: other |
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Source (natural) | Organism: ![]() |
Sequence | String: RPQGATVSLW ETVQKWREYR RQCQRSLTED PPPATDLFCN RTFDEYACWP DGEPGSFVNV SCPWYLPWAS SVPQGHVYRF CTAEGLWLQK DNSSLPWRDL SECEESKRGE RSSPEEQLLF LYIIYTVGYA LSFSALVIAS AILLGFRHLH CTRNYIHLNL FASFILRALS ...String: RPQGATVSLW ETVQKWREYR RQCQRSLTED PPPATDLFCN RTFDEYACWP DGEPGSFVNV SCPWYLPWAS SVPQGHVYRF CTAEGLWLQK DNSSLPWRDL SECEESKRGE RSSPEEQLLF LYIIYTVGYA LSFSALVIAS AILLGFRHLH CTRNYIHLNL FASFILRALS VFIKDAALKW MYSTAAQQHQ WDGLLSYQDS LSCRLVFLLM QYCVAANYYW LLVEGVYLYT LLAFSVLSEQ WIFRLYVSIG WGVPLLFVVP WGIVKYLYED EGCWTRNSNM NYWLIIRLPI LFAIGVNFLI FVRVICIVVS KLKANLMCKT DIKCRLAKST LTLIPLLGTH EVIFAFVMDE HARGTLRFIK LFTELSFTSF QGLMVAILYC FVNNEVQLEF RKSWERWRLE HLHIQRDSSM KPLKCPTSSL SSGATAGSSM YTATCQASCS MGCLGNSKT EDQRNEEKAQ REANKKIEKQ LQKDKQVYRA THRLLLLGAD NSGKSTIVKQ MRIYHVNSGI FETKFQVDKV NFHMFDVGAQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ AALKLFDSIW NNKWLRDTSV ILFLNKQDLL AEKVLAGKSK IEDYFPEFAR YTTPEDATPE PGEDPRVTRA KYFIRDEFLR ISTASGDGRH YCYPHFTCSV DTENIRRVFN DCRDIIQRMH LRQYELL MG SLLQSELDQL RQEAEQLKNQ IRDARKACAD ATLSQITNNI DPVGRIQMRT RRTLRGHLAK IYAMHWGTDS RLLVSASQDG KLIIWDSYTT NKVHAIPLRS SWVMTCAYAP SGNYVACGGL DNICSIYNLK TREGNVRVSR ELAGHTGYLS CCRFLDDNQI VTSSGDTTCA LWDIETGQQT TTFTGHTGDV MSLSLAPDTR LFVSGACDAS AKLWDVREGM CRQTFTGHES DINAICFFPN GNAFATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGVTDDGMAV ATGSWDSFLK IWN MASNNT ASIAQARKLV EQLKMEANID RIKVSKAAAD LMAYCEAHAK EDPLLTPVPA SENPFREKKF FCAIL QVQL QESGGGLVQP GGSLRLSCAA SGFTFSNYKM NWVRQAPGKG LEWVSDISQS GASISYTGSV KGRFTISRDN AKNTLYLQMN SLKPEDTAVY YCARCPAPFT RDCFDVTSTT YAYRGQGTQV TVSS |
Recombinant expression | Organism: Insect cell expression vector pTIE1 (others) |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | cell |
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Sample preparation
Concentration | 10 mg/mL |
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Buffer | pH: 7.5 |
Grid | Model: Quantifoil / Material: GOLD / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 101.325 kPa |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 80.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | C2 aperture diameter: 100.0 µm / Illumination mode: OTHER / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |