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- PDB-7fiy: Cryo-EM structure of the tirzepatide-bound human GIPR-Gs complex -

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Basic information

Entry
Database: PDB / ID: 7fiy
TitleCryo-EM structure of the tirzepatide-bound human GIPR-Gs complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Gastric inhibitory polypeptide receptor,Gastric inhibitory polypeptide receptor,human glucose-dependent insulinotropic polypeptide receptor
  • Nanobody-35
  • Tiezepatide
KeywordsSTRUCTURAL PROTEIN / Cryo-electron microscopy / G protein-coupled receptor / ligand recognition / receptor activation / unimolecular agonist
Function / homology
Function and homology information


gastric inhibitory peptide receptor activity / glucagon family peptide binding / gastric inhibitory peptide signaling pathway / endocrine pancreas development / positive regulation of cAMP-mediated signaling / sensory perception of chemical stimulus / desensitization of G protein-coupled receptor signaling pathway / mu-type opioid receptor binding / response to fatty acid / corticotropin-releasing hormone receptor 1 binding ...gastric inhibitory peptide receptor activity / glucagon family peptide binding / gastric inhibitory peptide signaling pathway / endocrine pancreas development / positive regulation of cAMP-mediated signaling / sensory perception of chemical stimulus / desensitization of G protein-coupled receptor signaling pathway / mu-type opioid receptor binding / response to fatty acid / corticotropin-releasing hormone receptor 1 binding / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / G protein-coupled peptide receptor activity / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (i) signalling events / alkylglycerophosphoethanolamine phosphodiesterase activity / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Glucagon-type ligand receptors / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / beta-2 adrenergic receptor binding / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / Extra-nuclear estrogen signaling / G alpha (z) signalling events / G alpha (s) signalling events / G alpha (q) signalling events / photoreceptor outer segment membrane / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (i) signalling events / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / peptide hormone binding / photoreceptor outer segment / D1 dopamine receptor binding / response to axon injury / response to glucose / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / cardiac muscle cell apoptotic process / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / adenylate cyclase activator activity / regulation of insulin secretion / photoreceptor inner segment / response to nutrient / generation of precursor metabolites and energy / G-protein beta/gamma-subunit complex binding / positive regulation of insulin secretion / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Glucagon-type ligand receptors / response to calcium ion / cellular response to catecholamine stimulus / sensory perception of taste / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / transmembrane signaling receptor activity / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / cellular response to hypoxia / cell body / G alpha (s) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / cell population proliferation / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / GTPase activity
Similarity search - Function
GPCR, family 2, gastric inhibitory polypeptide 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, gastric inhibitory polypeptide 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 / 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 / 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. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
CHOLESTEROL / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Gastric inhibitory polypeptide receptor / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Bos taurus (cattle)
Rattus norvegicus (Norway rat)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsZhao, F.H. / Zhou, Q.T. / Cong, Z.T. / Hang, K.N. / Zou, X.Y. / Zhang, C. / Chen, Y. / Dai, A.T. / Liang, A.Y. / Ming, Q.Q. ...Zhao, F.H. / Zhou, Q.T. / Cong, Z.T. / Hang, K.N. / Zou, X.Y. / Zhang, C. / Chen, Y. / Dai, A.T. / Liang, A.Y. / Ming, Q.Q. / Wang, M. / Chen, L.N. / Xu, P.Y. / Chang, R.L. / Feng, W.B. / Xia, T. / Zhang, Y. / Wu, B.L. / Yang, D.H. / Zhao, L.H. / Xu, H.E. / Wang, M.W.
Funding support China, 7items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81872915 China
National Natural Science Foundation of China (NSFC)82073904 China
National Natural Science Foundation of China (NSFC)32071203 China
National Natural Science Foundation of China (NSFC)81922071 China
National Natural Science Foundation of China (NSFC)81773792 China
National Natural Science Foundation of China (NSFC)81973373 China
National Natural Science Foundation of China (NSFC)81922071 (Y.Z.), 81773792 (D.Y.), 81973373 (D.Y.) and 21704064 (Q.Z.); National Science and Technology Major China
CitationJournal: Nat Commun / Year: 2022
Title: Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors.
Authors: Fenghui Zhao / Qingtong Zhou / Zhaotong Cong / Kaini Hang / Xinyu Zou / Chao Zhang / Yan Chen / Antao Dai / Anyi Liang / Qianqian Ming / Mu Wang / Li-Nan Chen / Peiyu Xu / Rulve Chang / ...Authors: Fenghui Zhao / Qingtong Zhou / Zhaotong Cong / Kaini Hang / Xinyu Zou / Chao Zhang / Yan Chen / Antao Dai / Anyi Liang / Qianqian Ming / Mu Wang / Li-Nan Chen / Peiyu Xu / Rulve Chang / Wenbo Feng / Tian Xia / Yan Zhang / Beili Wu / Dehua Yang / Lihua Zhao / H Eric Xu / Ming-Wei Wang /
Abstract: Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists ...Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists at GIPR, GLP-1R or GCGR, developed to maximize metabolic benefits with reduced side-effects, are in clinical trials to treat type 2 diabetes and obesity. To elucidate the molecular mechanisms by which tirzepatide, a GIPR/GLP-1R dual agonist, and peptide 20, a GIPR/GLP-1R/GCGR triagonist, manifest their multiplexed pharmacological actions over monoagonists such as semaglutide, we determine cryo-electron microscopy structures of tirzepatide-bound GIPR and GLP-1R as well as peptide 20-bound GIPR, GLP-1R and GCGR. The structures reveal both common and unique features for the dual and triple agonism by illustrating key interactions of clinical relevance at the near-atomic level. Retention of glucagon function is required to achieve such an advantage over GLP-1 monotherapy. Our findings provide valuable insights into the structural basis of functional versatility of tirzepatide and peptide 20.
History
DepositionAug 1, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 2, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 16, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation_author.name

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Structure visualization

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Assembly

Deposited unit
R: Gastric inhibitory polypeptide receptor,Gastric inhibitory polypeptide receptor,human glucose-dependent insulinotropic polypeptide receptor
P: Tiezepatide
A: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
N: Nanobody-35
hetero molecules


Theoretical massNumber of molelcules
Total (without water)180,51812
Polymers178,1986
Non-polymers2,3206
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

#3: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-stimulating G alpha protein


Mass: 45743.441 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: GNAS, GNAS1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P04896
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 40226.992 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gnb1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P54311
#5: 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.) Bos taurus (cattle) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63212

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Protein / Protein/peptide / Antibody / Non-polymers , 4 types, 9 molecules RPN

#1: Protein Gastric inhibitory polypeptide receptor,Gastric inhibitory polypeptide receptor,human glucose-dependent insulinotropic polypeptide receptor / GIP-R / Glucose-dependent insulinotropic polypeptide receptor


Mass: 64950.695 Da / Num. of mol.: 1 / Mutation: T345F
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
#2: Protein/peptide Tiezepatide


Mass: 4072.530 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: At positon of K20 attached C20 diacid-gama-Glu-(AEEA)2, which is a C20 fatty diacid moiety connected to the lysine residue via a linker. And there is a NH2 at the C terminus of the peptide.
Source: (synth.) synthetic construct (others)
#6: Antibody Nanobody-35


Mass: 15343.019 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)
#7: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C27H46O

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Details

Has ligand of interestN

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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

ComponentName: Cryo-EM structure of the tirzepatide-bound human GIPR-Gs complex
Type: COMPLEX / Entity ID: #1-#6 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: OTHER / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 80 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.4 Å / Resolution method: DIFFRACTION PATTERN/LAYERLINES / Num. of particles: 511557 / Symmetry type: POINT

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