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- PDB-7ra3: cryo-EM of human Gastric inhibitory polypeptide receptor GIPR bou... -

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Basic information

Entry
Database: PDB / ID: 7ra3
Titlecryo-EM of human Gastric inhibitory polypeptide receptor GIPR bound to GIP
Components
  • (Gastric inhibitory ...) x 2
  • (Guanine nucleotide-binding protein ...) x 3
  • Nanobody 35Single-domain antibody
  • Single-chain variable fragment 16
KeywordsMEMBRANE PROTEIN / Class B GPCR / glucagon-like peptide-1 receptor / G protein nucleotide exchange factor.
Function / homology
Function and homology information


gastric inhibitory polypeptide receptor binding / gastric inhibitory peptide receptor activity / glucagon family peptide binding / digestive system development / gastric inhibitory peptide signaling pathway / glucagon receptor binding / regulation of fatty acid biosynthetic process / desensitization of G protein-coupled receptor signaling pathway / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / endocrine pancreas development ...gastric inhibitory polypeptide receptor binding / gastric inhibitory peptide receptor activity / glucagon family peptide binding / digestive system development / gastric inhibitory peptide signaling pathway / glucagon receptor binding / regulation of fatty acid biosynthetic process / desensitization of G protein-coupled receptor signaling pathway / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / endocrine pancreas development / response to selenium ion / response to fatty acid / negative regulation of adenylate cyclase activity / triglyceride homeostasis / G protein-coupled peptide receptor activity / response to acidic pH / positive regulation of glucose transmembrane transport / GTP metabolic process / exploration behavior / dopamine receptor signaling pathway / response to lipid / response to starvation / PKA activation in glucagon signalling / peptide hormone binding / positive regulation of macroautophagy / regulation of insulin secretion / hair follicle placode formation / intracellular transport / Adenylate cyclase inhibitory pathway / D1 dopamine receptor binding / developmental growth / response to axon injury / response to amino acid / Hedgehog 'off' state / positive regulation of cAMP-mediated signaling / response to glucose / adenylate cyclase-activating adrenergic receptor signaling pathway / sensory perception of pain / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / activation of adenylate cyclase activity / adenylate cyclase activator activity / adult locomotory behavior / response to nutrient / trans-Golgi network membrane / generation of precursor metabolites and energy / long-term synaptic potentiation / G protein-coupled receptor binding / female pregnancy / G-protein beta/gamma-subunit complex binding / 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 / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / bone development / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / hormone activity / ADP signalling through P2Y purinoceptor 12 / positive regulation of insulin secretion / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / response to organic cyclic compound / response to peptide hormone / memory / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / platelet aggregation / Glucagon-type ligand receptors / cognition / Vasopressin regulates renal water homeostasis via Aquaporins / positive regulation of GTPase activity / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / response to calcium ion / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / GPER1 signaling / GDP binding / G-protein beta-subunit binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / G alpha (12/13) signalling events / transmembrane signaling receptor activity / signaling receptor complex adaptor activity
Similarity search - Function
Gastric inhibitory polypeptide / GPCR, family 2, gastric inhibitory polypeptide receptor / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones / G-protein coupled receptors family 2 signature 1. / Hormone receptor domain / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. ...Gastric inhibitory polypeptide / GPCR, family 2, gastric inhibitory polypeptide receptor / Glucagon/GIP/secretin/VIP / Peptide hormone / Glucagon / GIP / secretin / VIP family signature. / Glucagon like hormones / G-protein coupled receptors family 2 signature 1. / Hormone receptor domain / GPCR, family 2, extracellular hormone receptor domain / G-protein coupled receptors family 2 profile 1. / Domain present in hormone receptors / 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 / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / 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. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Guanine nucleotide-binding protein G(i) subunit alpha-3 / Gastric inhibitory polypeptide / Gastric inhibitory polypeptide 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: 3.24 Å
AuthorsSun, B. / Kobilka, B.K. / Sloop, K.W. / Feng, D. / Kobilka, T.S.
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
DepositionJun 29, 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: Gastric inhibitory polypeptide
R: Gastric inhibitory polypeptide receptor


Theoretical massNumber of molelcules
Total (without water)196,8667
Polymers196,8667
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area16920 Å2
ΔGint-88 kcal/mol
Surface area59980 Å2

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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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Gastric inhibitory ... , 2 types, 2 molecules PR

#6: Protein/peptide Gastric inhibitory polypeptide / / GIP / Glucose-dependent insulinotropic polypeptide / Incretin hormone


Mass: 4990.586 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P09681
#7: Protein Gastric inhibitory polypeptide receptor / / GIP-R / Glucose-dependent insulinotropic polypeptide receptor


Mass: 52871.801 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GIPR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P48546

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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 / Single-domain antibody


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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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 Gastric inhibitory polypeptide receptor GIPR bound to GIP, trimeric G protein complex and stabilizing antibodiesCOMPLEXall0RECOMBINANT
2Gastric inhibitory polypeptide GIP bound to GIP receptor GIPRCOMPLEX#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 FIELDBright-field microscopy / 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
13RELION33D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.24 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 145195 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT
Atomic model buildingPDB-ID: 6VCB

6vcb

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