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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 / hormone secretion / negative regulation of adenylate cyclase activity / post-translational protein targeting to membrane, translocation / GTP metabolic process / response to psychosocial stress / regulation of heart contraction / peptide hormone binding ...glucagon-like peptide 1 receptor activity / glucagon receptor activity / positive regulation of blood pressure / hormone secretion / negative regulation of adenylate cyclase activity / post-translational protein targeting to membrane, translocation / GTP metabolic process / response to psychosocial stress / regulation of heart contraction / peptide hormone binding / positive regulation of macroautophagy / PKA activation in glucagon signalling / developmental growth / hair follicle placode formation / D1 dopamine receptor binding / intracellular transport / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / activation of adenylate cyclase activity / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / negative regulation of blood pressure / Adenylate cyclase inhibitory pathway / cellular response to glucagon stimulus / regulation of insulin secretion / adenylate cyclase activator activity / trans-Golgi network membrane / negative regulation of inflammatory response to antigenic stimulus / G protein-coupled receptor binding / bone development / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / platelet aggregation / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / centriolar satellite / cognition / G-protein beta/gamma-subunit complex binding / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / GDP binding / Vasopressin regulates renal water homeostasis via Aquaporins / sensory perception of smell / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / transmembrane signaling receptor activity / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / positive regulation of cold-induced thermogenesis / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / positive regulation of cytosolic calcium ion concentration / G protein activity / GTPase binding / Ca2+ pathway / fibroblast proliferation / midbody / 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 / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Ras protein signal transduction / learning or memory / cell surface receptor signaling pathway / Extra-nuclear estrogen signaling / cell population proliferation / ciliary basal body / G protein-coupled receptor signaling pathway / lysosomal membrane
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 / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / 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

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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

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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

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