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- EMDB-24334: cryo-EM of human Gastric inhibitory polypeptide receptor GIPR bou... -
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Basic information
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Title | cryo-EM of human Gastric inhibitory polypeptide receptor GIPR bound to GIP | |||||||||
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Function / homology | ![]() 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 / desensitization of G protein-coupled receptor signaling pathway / regulation of fatty acid biosynthetic process / endocrine pancreas development / positive regulation of cAMP-mediated signaling ...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 / desensitization of G protein-coupled receptor signaling pathway / regulation of fatty acid biosynthetic process / endocrine pancreas development / positive regulation of cAMP-mediated signaling / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / response to selenium ion / response to fatty acid / negative regulation of adenylate cyclase activity / G protein-coupled peptide receptor activity / response to acidic pH / positive regulation of glucose transmembrane transport / GTP metabolic process / triglyceride homeostasis / exploration behavior / G protein-coupled dopamine receptor signaling pathway / response to lipid / response to starvation / peptide hormone binding / PKA activation in glucagon signalling / regulation of insulin secretion / hair follicle placode formation / positive regulation of macroautophagy / developmental growth / D1 dopamine receptor binding / intracellular transport / response to axon injury / Adenylate cyclase inhibitory pathway / response to amino acid / Hedgehog 'off' state / response to glucose / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / sensory perception of pain / adenylate cyclase activator activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adult locomotory behavior / response to nutrient / trans-Golgi network membrane / generation of precursor metabolites and energy / G protein-coupled receptor binding / female pregnancy / long-term synaptic potentiation / G-protein beta/gamma-subunit complex binding / bone development / 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 / positive regulation of insulin secretion / Thromboxane signalling through TP receptor / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / hormone activity / response to organic cyclic compound / 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 / memory / cognition / platelet aggregation / response to peptide hormone / 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 / transmembrane signaling receptor activity / GPER1 signaling / GDP binding / 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 / sensory perception of smell / signaling receptor complex adaptor activity Similarity search - Function | |||||||||
Biological species | ![]() ![]() ![]() ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.24 Å | |||||||||
![]() | Sun B / Kobilka BK / Sloop KW / Feng D / Kobilka TS | |||||||||
![]() | ![]() 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. | |||||||||
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Structure visualization
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Downloads & links
-EMDB archive
Map data | ![]() | 226.1 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 20.9 KB 20.9 KB | Display Display | ![]() |
Images | ![]() | 106.1 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7ra3MC ![]() 7rbtC ![]() 7rg9C ![]() 7rgpC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 0.648 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
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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: Gastric inhibitory polypeptide GIP bound to GIP receptor GIPR
+Supramolecule #3: Trimeric stimulatory G protein
+Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-3,Isoform G...
+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: Gastric inhibitory polypeptide
+Macromolecule #7: Gastric inhibitory polypeptide receptor
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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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 |
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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: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |