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- EMDB-23436: Oxyntomodulin-bound Glucagon-Like Peptide-1 (GLP-1) Receptor in c... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-23436 | ||||||||||||||||||
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Title | Oxyntomodulin-bound Glucagon-Like Peptide-1 (GLP-1) Receptor in complex with Gs protein | ||||||||||||||||||
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Function / homology | ![]() Glucagon signaling in metabolic regulation / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (s) signalling events / Glucagon-type ligand receptors / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / G alpha (q) signalling events / Synthesis, secretion, and deacylation of Ghrelin / glucagon receptor binding / glucagon-like peptide 1 receptor activity / glucagon receptor activity ...Glucagon signaling in metabolic regulation / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (s) signalling events / Glucagon-type ligand receptors / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / G alpha (q) signalling events / Synthesis, secretion, and deacylation of Ghrelin / glucagon receptor binding / glucagon-like peptide 1 receptor activity / glucagon receptor activity / hormone secretion / positive regulation of blood pressure / post-translational protein targeting to membrane, translocation / response to psychosocial stress / regulation of heart contraction / positive regulation of insulin secretion involved in cellular response to glucose stimulus / peptide hormone binding / PKA activation in glucagon signalling / regulation of insulin secretion / hair follicle placode formation / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / developmental growth / D1 dopamine receptor binding / intracellular transport / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / beta-2 adrenergic receptor binding / protein kinase A signaling / adenylate cyclase activator activity / negative regulation of blood pressure / cAMP-mediated signaling / trans-Golgi network membrane / response to activity / insulin-like growth factor receptor binding / ionotropic glutamate receptor binding / G-protein beta/gamma-subunit complex binding / bone development / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / hormone activity / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / cognition / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / platelet aggregation / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / transmembrane signaling receptor activity / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / sensory perception of smell / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / glucose homeostasis / Ca2+ pathway / positive regulation of cold-induced thermogenesis / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / learning or memory / cell surface receptor signaling pathway Similarity search - Function | ||||||||||||||||||
Biological species | ![]() ![]() ![]() ![]() ![]() | ||||||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.3 Å | ||||||||||||||||||
![]() | Wootten D / Sexton PM / Belousoff MJ / Danev R / Zhang X / Khoshouei M / Venugopal H | ||||||||||||||||||
Funding support | ![]() ![]()
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![]() | ![]() Title: Dynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation. Authors: Giuseppe Deganutti / Yi-Lynn Liang / Xin Zhang / Maryam Khoshouei / Lachlan Clydesdale / Matthew J Belousoff / Hari Venugopal / Tin T Truong / Alisa Glukhova / Andrew N Keller / Karen J ...Authors: Giuseppe Deganutti / Yi-Lynn Liang / Xin Zhang / Maryam Khoshouei / Lachlan Clydesdale / Matthew J Belousoff / Hari Venugopal / Tin T Truong / Alisa Glukhova / Andrew N Keller / Karen J Gregory / Katie Leach / Arthur Christopoulos / Radostin Danev / Christopher A Reynolds / Peishen Zhao / Patrick M Sexton / Denise Wootten / ![]() ![]() ![]() ![]() ![]() ![]() Abstract: The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, ...The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, detailed mechanistic understanding of how different peptides generate profound differences in G protein-mediated signalling is still lacking. Here we combine cryo-electron microscopy, molecular dynamics simulations, receptor mutagenesis and pharmacological assays, to interrogate the mechanism and consequences of GLP-1R binding to four peptide agonists; glucagon-like peptide-1, oxyntomodulin, exendin-4 and exendin-P5. These data reveal that distinctions in peptide N-terminal interactions and dynamics with the GLP-1R transmembrane domain are reciprocally associated with differences in the allosteric coupling to G proteins. In particular, transient interactions with residues at the base of the binding cavity correlate with enhanced kinetics for G protein activation, providing a rationale for differences in G protein-mediated signalling efficacy from distinct agonists. | ||||||||||||||||||
History |
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Structure visualization
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 3.6 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 22.1 KB 22.1 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 6.5 KB | Display | ![]() |
Images | ![]() | 84.6 KB | ||
Masks | ![]() | 22.2 MB | ![]() | |
Others | ![]() ![]() | 17 MB 17 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7llyMC ![]() 7lllC 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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Annotation | postprocess map | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.06 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
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Density Histograms |
-Half map: half map 1
File | emd_23436_half_map_1.map | ||||||||||||
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Density Histograms |
-Half map: half map 2
File | emd_23436_half_map_2.map | ||||||||||||
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Annotation | half map 2 | ||||||||||||
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Sample components
-Entire : Oxyntomodulin-GLP-1R-Gs complex
Entire | Name: Oxyntomodulin-GLP-1R-Gs complex |
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Components |
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-Supramolecule #1: Oxyntomodulin-GLP-1R-Gs complex
Supramolecule | Name: Oxyntomodulin-GLP-1R-Gs complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: ![]() |
Recombinant expression | Organism: ![]() |
-Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Macromolecule | Name: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 45.683434 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE ...String: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE YQLIDCAQYF LDKIDVIKQA DYVPSDQDLL RCRVLTSGIF ETKFQVDKVN FHMFDVGAQR DERRKWIQCF ND VTAIIFV VASSSYNMVI REDNQTNRLQ AALKLFDSIW NNKWLRDTSV ILFLNKQDLL AEKVLAGKSK IEDYFPEFAR YTT PEDATP EPGEDPRVTR AKYFIRDEFL RISTASGDGR HYCYPHFTCA VDTENIRRVF NDCRDIIQRM HLRQYELL |
-Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 37.413863 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: QSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...String: QSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD INAICFFPNG NA FATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGV TDDGMA VATGSWDSFL KIWN |
-Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 6.375332 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: NTASIAQARK LVEQLKMEAN IDRIKVSKAA ADLMAYCEAH AKEDPLLTPV PASENPFR |
-Macromolecule #4: Nb35
Macromolecule | Name: Nb35 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 13.885439 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: QVQLQESGGG LVQPGGSLRL SCAASGFTFS NYKMNWVRQA PGKGLEWVSD ISQSGASISY TGSVKGRFTI SRDNAKNTLY LQMNSLKPE DTAVYYCARC PAPFTRDCFD VTSTTYAYRG QGTQVTVSS |
-Macromolecule #5: Pro-glucagon
Macromolecule | Name: Pro-glucagon / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 4.428878 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: HSQGTFTSDY SKYLDSRRAQ DFVQWLMNTK RNKNNIA |
-Macromolecule #6: Glucagon-like peptide 1 receptor
Macromolecule | Name: Glucagon-like peptide 1 receptor / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 56.748418 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MKTIIALSYI FCLVFADYKD DDDLEVLFQG PARPQGATVS LWETVQKWRE YRRQCQRSLT EDPPPATDLF CNRTFDEYAC WPDGEPGSF VNVSCPWYLP WASSVPQGHV YRFCTAEGLW LQKDNSSLPW RDLSECEESK RGERSSPEEQ LLFLYIIYTV G YALSFSAL ...String: MKTIIALSYI FCLVFADYKD DDDLEVLFQG PARPQGATVS LWETVQKWRE YRRQCQRSLT EDPPPATDLF CNRTFDEYAC WPDGEPGSF VNVSCPWYLP WASSVPQGHV YRFCTAEGLW LQKDNSSLPW RDLSECEESK RGERSSPEEQ LLFLYIIYTV G YALSFSAL VIASAILLGF RHLHCTRNYI HLNLFASFIL RALSVFIKDA ALKWMYSTAA QQHQWDGLLS YQDSLSCRLV FL LMQYCVA ANYYWLLVEG VYLYTLLAFS VFSEQWIFRL YVSIGWGVPL LFVVPWGIVK YLYEDEGCWT RNSNMNYWLI IRL PILFAI GVNFLIFVRV ICIVVSKLKA NLMCKTDIKC RLAKSTLTLI PLLGTHEVIF AFVMDEHARG TLRFIKLFTE LSFT SFQGL MVAILYCFVN NEVQLEFRKS WERWRLEHLH IQRDSSMKPL KCPTSSLSSG ATAGSSMYTA TCQASCSPAG LEVLF QGPH HHHHHHH |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Phase plate: VOLTA PHASE PLATE Spherical aberration corrector: Non-Cs corrected microscope with a Cs=2.7 mm |
Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |