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Yorodumi- PDB-7rbt: cryo-EM structure of human Gastric inhibitory polypeptide recepto... -
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-Basic information
Entry | Database: PDB / ID: 7rbt | ||||||
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Title | cryo-EM structure of human Gastric inhibitory polypeptide receptor GIPR bound to tirzepatide | ||||||
Components |
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Keywords | MEMBRANE PROTEIN / Class B GPCR / glucagon-like peptide-1 receptor / G protein nucleotide exchange factor. | ||||||
Function / homology | Function and homology information gastric inhibitory peptide receptor activity / glucagon family peptide binding / gastric inhibitory peptide signaling pathway / desensitization of G protein-coupled receptor signaling pathway / positive regulation of cAMP-mediated signaling / endocrine pancreas development / response to fatty acid / G protein-coupled peptide receptor activity / peptide hormone binding / regulation of insulin secretion ...gastric inhibitory peptide receptor activity / glucagon family peptide binding / gastric inhibitory peptide signaling pathway / desensitization of G protein-coupled receptor signaling pathway / positive regulation of cAMP-mediated signaling / endocrine pancreas development / response to fatty acid / G protein-coupled peptide receptor activity / peptide hormone binding / regulation of insulin secretion / response to axon injury / response to glucose / activation of adenylate cyclase activity / response to nutrient / generation of precursor metabolites and energy / 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 / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of insulin secretion / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / 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 / 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 / response to calcium ion / 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 / GPER1 signaling / transmembrane signaling receptor activity / 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 / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / G alpha (i) signalling events / positive regulation of cytosolic calcium ion concentration / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytoplasm / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) Mus musculus (house mouse) Lama glama (llama) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.08 Å | ||||||
Authors | Sun, B. / Kobilka, B.K. / Sloop, K.W. / Feng, D. / Kobilka, T.S. | ||||||
Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7rbt.cif.gz | 260 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7rbt.ent.gz | 206.4 KB | Display | PDB format |
PDBx/mmJSON format | 7rbt.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 7rbt_validation.pdf.gz | 998.9 KB | Display | wwPDB validaton report |
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Full document | 7rbt_full_validation.pdf.gz | 1 MB | Display | |
Data in XML | 7rbt_validation.xml.gz | 46 KB | Display | |
Data in CIF | 7rbt_validation.cif.gz | 69.4 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/rb/7rbt ftp://data.pdbj.org/pub/pdb/validation_reports/rb/7rbt | HTTPS FTP |
-Related structure data
Related structure data | 24401MC 7ra3C 7rg9C 7rgpC C: citing same article (ref.) M: map data used to model this data |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 2 types, 2 molecules AR
#1: Protein | Mass: 43385.246 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P63092-2 |
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#7: Protein | 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 |
-Guanine nucleotide-binding protein ... , 2 types, 2 molecules BG
#2: Protein | 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 |
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#4: Protein | 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: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768 |
-Antibody , 2 types, 2 molecules EN
#3: Antibody | 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) |
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#5: 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) |
-Protein/peptide / Non-polymers , 2 types, 2 molecules P
#6: Protein/peptide | Mass: 4072.530 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: With designed modification. / Source: (synth.) Homo sapiens (human) |
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#8: Chemical | ChemComp-41Y / |
-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
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Buffer solution | pH: 7.5 | ||||||||||||||||||||||||
Specimen | Conc.: 10 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 293 K |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Cs: 2.7 mm |
Image recording | Average 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 optics | Energyfilter name: GIF Quantum LS / Energyfilter slit width: 20 eV |
Image scans | Movie frames/image: 50 |
-Processing
Software |
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.08 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 259349 / Symmetry type: POINT | ||||||||||||||||||||||||
Atomic model building | Protocol: FLEXIBLE FIT | ||||||||||||||||||||||||
Atomic model building | PDB-ID: 6VCB | ||||||||||||||||||||||||
Refinement | Cross valid method: NONE Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
Displacement parameters | Biso mean: 59.94 Å2 | ||||||||||||||||||||||||
Refine LS restraints |
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