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Yorodumi- EMDB-24401: cryo-EM structure of human Gastric inhibitory polypeptide recepto... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-24401 | |||||||||
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Title | cryo-EM structure of human Gastric inhibitory polypeptide receptor GIPR bound to tirzepatide | |||||||||
Map data | ||||||||||
Sample |
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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 / response to calcium ion / 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 / 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 | single particle reconstruction / cryo EM / Resolution: 3.08 Å | |||||||||
Authors | Sun B / Kobilka BK / Sloop KW / Feng D / Kobilka TS | |||||||||
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
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_24401.map.gz | 96.5 MB | EMDB map data format | |
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Header (meta data) | emd-24401-v30.xml emd-24401.xml | 21.3 KB 21.3 KB | Display Display | EMDB header |
Images | emd_24401.png | 113.1 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-24401 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-24401 | HTTPS FTP |
-Validation report
Summary document | emd_24401_validation.pdf.gz | 507.7 KB | Display | EMDB validaton report |
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Full document | emd_24401_full_validation.pdf.gz | 507.3 KB | Display | |
Data in XML | emd_24401_validation.xml.gz | 6.2 KB | Display | |
Data in CIF | emd_24401_validation.cif.gz | 7 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-24401 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-24401 | HTTPS FTP |
-Related structure data
Related structure data | 7rbtMC 7ra3C 7rg9C 7rgpC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_24401.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 0.832 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Sample components
+Entire : cryo-EM of human Gastric inhibitory polypeptide receptor GIPR bou...
+Supramolecule #1: cryo-EM of human Gastric inhibitory polypeptide receptor GIPR bou...
+Supramolecule #2: Tirzepatide bound to GIP receptor GIPR
+Supramolecule #3: Trimeric stimulatory G protein
+Macromolecule #1: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit...
+Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
+Macromolecule #3: Single-chain variable fragment 16
+Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
+Macromolecule #5: nanobody 35
+Macromolecule #6: Tirzepatide
+Macromolecule #7: Gastric inhibitory polypeptide receptor
+Macromolecule #8: 2-fluoro-4-[(1R)-6-methoxy-1-methyl-2-{(1S)-1-[4-(propan-2-yl)phe...
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 10 mg/mL |
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Buffer | pH: 7.5 |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 293 K / Instrument: FEI VITROBOT MARK IV |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Name: GIF Quantum LS / Energy filter - Slit width: 20 eV |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Detector mode: COUNTING / Average exposure time: 1.5 sec. / Average electron dose: 53.6 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |