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- PDB-7rgp: cryo-EM of human Glucagon-like peptide 1 receptor GLP-1R bound to... -

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Basic information

Entry
Database: PDB / ID: 7rgp
Titlecryo-EM of human Glucagon-like peptide 1 receptor GLP-1R bound to tirzepatide
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Glucagon-like peptide 1 receptor
  • Single-chain variable fragment 16
  • Tirzepatide
  • nanobody 35
KeywordsMEMBRANE PROTEIN / Class B GPCR / glucagon-like peptide-1 receptor / G protein nucleotide exchange factor.
Function / homology
Function and homology information


glucagon-like peptide 1 receptor activity / glucagon receptor activity / positive regulation of blood pressure / negative regulation of adenylate cyclase activity / GTP metabolic process / regulation of heart contraction / response to psychosocial stress / adenylate cyclase-activating G protein-coupled bile acid receptor signaling pathway / adenylate cyclase-activating serotonin receptor signaling pathway / positive regulation of macroautophagy ...glucagon-like peptide 1 receptor activity / glucagon receptor activity / positive regulation of blood pressure / negative regulation of adenylate cyclase activity / GTP metabolic process / regulation of heart contraction / response to psychosocial stress / adenylate cyclase-activating G protein-coupled bile acid receptor signaling pathway / adenylate cyclase-activating serotonin receptor signaling pathway / positive regulation of macroautophagy / peptide hormone binding / regulation of skeletal muscle contraction / hair follicle placode formation / developmental growth / PKA activation in glucagon signalling / intracellular transport / D1 dopamine receptor binding / renal water homeostasis / vascular endothelial cell response to laminar fluid shear stress / Hedgehog 'off' state / activation of adenylate cyclase activity / adenylate cyclase-activating adrenergic receptor signaling pathway / cellular response to acidic pH / Adenylate cyclase inhibitory pathway / cellular response to glucagon stimulus / intracellular glucose homeostasis / adenylate cyclase activator activity / positive regulation of insulin secretion involved in cellular response to glucose stimulus / trans-Golgi network membrane / negative regulation of inflammatory response to antigenic stimulus / response to prostaglandin E / bone development / positive regulation of insulin secretion / platelet aggregation / G protein-coupled receptor binding / cognition / G-protein beta/gamma-subunit complex binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / sensory perception of smell / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / GDP binding / G beta:gamma signalling through BTK / photoreceptor disc membrane / ADP signalling through P2Y purinoceptor 12 / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / Adrenaline,noradrenaline inhibits insulin secretion / transmembrane signaling receptor activity / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / positive regulation of cold-induced thermogenesis / GPER1 signaling / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / G alpha (12/13) signalling events / G-protein beta-subunit binding / positive regulation of cytosolic calcium ion concentration / extracellular vesicle / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / GTPase binding / G protein activity / midbody / Ca2+ pathway / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / learning or memory / Ras protein signal transduction / ciliary basal body / cell surface receptor signaling pathway / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / centrosome
Similarity search - Function
GPCR, family 2, glucagon-like peptide-1 receptor / : / GPCR, family 2, glucagon-like peptide-1/glucagon receptor / G-protein coupled receptors family 2 signature 1. / : / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / Hormone receptor domain / GPCR family 2, extracellular hormone receptor domain superfamily ...GPCR, family 2, glucagon-like peptide-1 receptor / : / GPCR, family 2, glucagon-like peptide-1/glucagon receptor / G-protein coupled receptors family 2 signature 1. / : / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / Hormone receptor domain / GPCR family 2, extracellular hormone receptor domain superfamily / G-protein coupled receptors family 2 signature 2. / GPCR, family 2, secretin-like, conserved site / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / G-protein alpha subunit, group S / YVTN repeat-like/Quinoprotein amine dehydrogenase / G-protein alpha subunit, group I / 7 Propeller / Methylamine Dehydrogenase; Chain H / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
Guanine nucleotide-binding protein G(i) subunit alpha-3 / Glucagon-like peptide 1 receptor / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsSun, B. / Kobilka, B.K. / Sloop, K.W. / Feng, D. / Kobilka, T.S.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2022
Title: Structural determinants of dual incretin receptor agonism by tirzepatide.
Authors: Bingfa Sun / Francis S Willard / Dan Feng / Jorge Alsina-Fernandez / Qi Chen / Michal Vieth / Joseph D Ho / Aaron D Showalter / Cynthia Stutsman / Liyun Ding / Todd M Suter / James D Dunbar ...Authors: Bingfa Sun / Francis S Willard / Dan Feng / Jorge Alsina-Fernandez / Qi Chen / Michal Vieth / Joseph D Ho / Aaron D Showalter / Cynthia Stutsman / Liyun Ding / Todd M Suter / James D Dunbar / John W Carpenter / Faiz Ahmad Mohammed / Eitaro Aihara / Robert A Brown / Ana B Bueno / Paul J Emmerson / Julie S Moyers / Tong Sun Kobilka / Matthew P Coghlan / Brian K Kobilka / Kyle W Sloop /
Abstract: SignificanceTirzepatide is a dual agonist of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R), which are incretin receptors that ...SignificanceTirzepatide is a dual agonist of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R), which are incretin receptors that regulate carbohydrate metabolism. This investigational agent has proven superior to selective GLP-1R agonists in clinical trials in subjects with type 2 diabetes mellitus. Intriguingly, although tirzepatide closely resembles native GIP in how it activates the GIPR, it differs markedly from GLP-1 in its activation of the GLP-1R, resulting in less agonist-induced receptor desensitization. We report how cryogenic electron microscopy and molecular dynamics simulations inform the structural basis for the unique pharmacology of tirzepatide. These studies reveal the extent to which fatty acid modification, combined with amino acid sequence, determines the mode of action of a multireceptor agonist.
History
DepositionJul 15, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 13, 2022Provider: repository / Type: Initial release
Revision 1.0Apr 13, 2022Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 13, 2022Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 13, 2022Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Mar 4, 2026Group: Data collection / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_fitting_list / em_admin / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.1Mar 4, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / EM metadata
Group: Data processing / Experimental summary / Refinement description
Data content type: EM metadata / EM metadata / EM metadata
Category: em_3d_fitting_list / em_admin / pdbx_initial_refinement_model
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-3,Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
E: Single-chain variable fragment 16
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
N: nanobody 35
P: Tirzepatide
R: Glucagon-like peptide 1 receptor


Theoretical massNumber of molelcules
Total (without water)194,3097
Polymers194,3097
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#1: Protein Guanine nucleotide-binding protein G(i) subunit alpha-3,Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / G(i) alpha-3 / Adenylate cyclase-stimulating G alpha protein


Mass: 43385.246 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI3, GNAS, GNAS1, GSP / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P08754, UniProt: P63092
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38534.062 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P62873
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P59768

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Antibody , 2 types, 2 molecules EN

#3: Antibody Single-chain variable fragment 16


Mass: 31870.629 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#5: Antibody nanobody 35


Mass: 17352.498 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)

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Protein/peptide / Protein , 2 types, 2 molecules PR

#6: Protein/peptide Tirzepatide


Mass: 4072.530 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#7: Protein Glucagon-like peptide 1 receptor / GLP-1R


Mass: 51233.109 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GLP1R / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P43220

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1cryo-EM of human Glucagon-like peptide 1 receptor GLP-1R bound to tirzepatide, trimeric G protein complex and stabilizing antibodiesCOMPLEXall0RECOMBINANT
2Glucagon-like peptide 1 receptor bound to tirzepatideCOMPLEX#6-#71MULTIPLE SOURCES
3Trimeric stimulatory G proteinCOMPLEX#1-#2, #41RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.15 MDaNO
210.15 MDaNO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
23Spodoptera frugiperda (fall armyworm)7108
12synthetic construct (others)32630
Buffer solutionpH: 7.5
SpecimenConc.: 10 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 293 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: -2500 nm / Nominal defocus min: -1100 nm / Cs: 2.7 mm
Image recordingAverage exposure time: 1.5 sec. / Electron dose: 53.6 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K3 (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Quantum LS / Energyfilter slit width: 20 eV
Image scansMovie frames/image: 50

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Processing

EM software
IDNameVersionCategory
4RELION3CTF correction
7PHENIX1.13model fitting
9PHENIX1.13model refinement
13RELION3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 340279 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT
Atomic model buildingPDB-ID: 6VCB

6vcb


Accession code: 6VCB / Source name: PDB / Type: experimental model

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