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Yorodumi- EMDB-31880: Cryo-EM structure of the non-acylated tirzepatide (LY3298176)-bou... -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-31880 | ||||||||||||||||||||||||
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Title | Cryo-EM structure of the non-acylated tirzepatide (LY3298176)-bound human GLP-1R-Gs complex | ||||||||||||||||||||||||
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Sample |
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Function / homology | Function and homology information glucagon-like peptide 1 receptor activity / glucagon receptor activity / hormone secretion / positive regulation of blood pressure / 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 ...glucagon-like peptide 1 receptor activity / glucagon receptor activity / hormone secretion / positive regulation of blood pressure / 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 / post-translational protein targeting to membrane, translocation / Vasopressin regulates renal water homeostasis via Aquaporins / 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) / 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 (i) signalling events / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / alkylglycerophosphoethanolamine phosphodiesterase activity / 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 / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / regulation of heart contraction / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / response to psychosocial stress / peptide hormone binding / photoreceptor outer segment / activation of adenylate cyclase activity / cardiac muscle cell apoptotic process / cAMP-mediated signaling / negative regulation of blood pressure / photoreceptor inner segment / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Glucagon-type ligand receptors / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / 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 / learning or memory / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / GTPase activity / dendrite / synapse / protein-containing complex binding / membrane / plasma membrane / cytoplasm Similarity search - Function | ||||||||||||||||||||||||
Biological species | Homo sapiens (human) / Escherichia coli (E. coli) / Rattus norvegicus (Norway rat) / Bos taurus (cattle) | ||||||||||||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.0 Å | ||||||||||||||||||||||||
Authors | Zhao FH / Zhou QT / Cong ZT / Hang KN / Zou XY / Zhang C / Chen Y / Dai AT / Liang AY / Ming QQ ...Zhao FH / Zhou QT / Cong ZT / Hang KN / Zou XY / Zhang C / Chen Y / Dai AT / Liang AY / Ming QQ / Wang M / Chen LN / Xu PY / Chang RL / Feng WB / Xia T / Zhang Y / Wu BL / Yang DH / Zhao LH / Xu HE / Wang MW | ||||||||||||||||||||||||
Funding support | China, 7 items
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Citation | Journal: 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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_31880.map.gz | 59.7 MB | EMDB map data format | |
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Header (meta data) | emd-31880-v30.xml emd-31880.xml | 18.1 KB 18.1 KB | Display Display | EMDB header |
Images | emd_31880.png | 54.8 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-31880 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-31880 | HTTPS FTP |
-Validation report
Summary document | emd_31880_validation.pdf.gz | 400.4 KB | Display | EMDB validaton report |
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Full document | emd_31880_full_validation.pdf.gz | 400 KB | Display | |
Data in XML | emd_31880_validation.xml.gz | 6.2 KB | Display | |
Data in CIF | emd_31880_validation.cif.gz | 7.1 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-31880 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-31880 | HTTPS FTP |
-Related structure data
Related structure data | 7vbiMC 7fimC 7finC 7fiyC 7v35C 7vabC 7vbhC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_31880.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.071 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
-Entire : Cryo-EM structure of the human glucagon-like peptide-1 receptor i...
Entire | Name: Cryo-EM structure of the human glucagon-like peptide-1 receptor in complex with non-acylated_tirzepatide and G protein |
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Components |
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-Supramolecule #1: Cryo-EM structure of the human glucagon-like peptide-1 receptor i...
Supramolecule | Name: Cryo-EM structure of the human glucagon-like peptide-1 receptor in complex with non-acylated_tirzepatide and G protein type: complex / ID: 1 / Parent: 0 / Macromolecule list: all |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
-Macromolecule #1: Isoform 3 of Guanine nucleotide-binding protein G(s) subunit alph...
Macromolecule | Name: Isoform 3 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 41.708273 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: QRNEEKAQRE ANKKIEKQLQ KDKQVYRATH RLLLLGAGES GKNTIVKQMR ILHVNGFNGD EKATKVQDIK NNLKEAIETI VAAMSNLVP PVELANPENQ FRVDYILSVM NVPDFDFPPE FYEHAKALWE DEGVRACYER SNEYQLIDCA QYFLDKIDVI K QADYVPSD ...String: QRNEEKAQRE ANKKIEKQLQ KDKQVYRATH RLLLLGAGES GKNTIVKQMR ILHVNGFNGD EKATKVQDIK NNLKEAIETI VAAMSNLVP PVELANPENQ FRVDYILSVM NVPDFDFPPE FYEHAKALWE DEGVRACYER SNEYQLIDCA QYFLDKIDVI K QADYVPSD QDLLRCRVLT SGIFETKFQV DKVNFHMFDV GAQRDERRKW IQCFNDVTAI IFVVASSTNR LQAALKLFDS IW NNKWLRD TSVILFLNKQ DLLAEKVLAG KSKIEDYFPE FARYTTPEDA TPEPGEDPRV TRAKYFIRDE FLRISTASGD GRH YCYPHF TCAVDTENIR RVFNDCRDII QRMHLRQYEL L |
-Macromolecule #2: Nanobody 35
Macromolecule | Name: Nanobody 35 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Escherichia coli (E. coli) |
Molecular weight | Theoretical: 15.343019 KDa |
Recombinant expression | Organism: Escherichia coli (E. coli) |
Sequence | String: MAQVQLQESG GGLVQPGGSL RLSCAASGFT FSNYKMNWVR QAPGKGLEWV SDISQSGASI SYTGSVKGRF TISRDNAKNT LYLQMNSLK PEDTAVYYCA RCPAPFTRDC FDVTSTTYAY RGQGTQVTVS SHHHHHHEPE A |
-Macromolecule #3: Non-acylated_tirzepatide
Macromolecule | Name: Non-acylated_tirzepatide / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 3.237657 KDa |
Sequence | String: Y(AIB)EGTFTSDY SI(AIB)LDKIAQK AFVQWLIAG |
-Macromolecule #4: Glucagon-like peptide 1 receptor
Macromolecule | Name: Glucagon-like peptide 1 receptor / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 50.860801 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: RPQGATVSLW ETVQKWREYR RQCQRSLTED PPPATDLFCN RTFDEYACWP DGEPGSFVNV SCPWYLPWAS SVPQGHVYRF CTAEGLWLQ KDNSSLPWRD LSECEESKRG ERSSPEEQLL FLYIIYTVGY ALSFSALVIA SAILLGFRHL HCTRNYIHLN L FASFILRA ...String: RPQGATVSLW ETVQKWREYR RQCQRSLTED PPPATDLFCN RTFDEYACWP DGEPGSFVNV SCPWYLPWAS SVPQGHVYRF CTAEGLWLQ KDNSSLPWRD LSECEESKRG ERSSPEEQLL FLYIIYTVGY ALSFSALVIA SAILLGFRHL HCTRNYIHLN L FASFILRA LSVFIKDAAL KWMYSTAAQQ HQWDGLLSYQ DSLSCRLVFL LMQYCVAANY YWLLVEGVYL YTLLAFSVLS EQ WIFRLYV SIGWGVPLLF VVPWGIVKYL YEDEGCWTRN SNMNYWLIIR LPILFAIGVN FLIFVRVICI VVSKLKANLM CKT DIKCRL AKSTLTLIPL LGTHEVIFAF VMDEHARGTL RFIKLFTELS FTSFQGLMVA ILYCFVNNEV QLEFRKSWER WRLE HLHIQ RDSSMKPLKC PTSSLSSGAT AGSSMYTATC QASCS |
-Macromolecule #5: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Rattus norvegicus (Norway rat) |
Molecular weight | Theoretical: 37.915496 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD ...String: MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD TTCALWDIET GQQTTTFTGH TGDVMSLSLA PDTRLFVSGA CDASAKLWDV REGMCRQTFT GHESDINAIC FF PNGNAFA TGSDDATCRL FDLRADQELM TYSHDNIICG ITSVSFSKSG RLLLAGYDDF NCNVWDALKA DRAGVLAGHD NRV SCLGVT DDGMAVATGS WDSFLKIWN |
-Macromolecule #6: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Bos taurus (cattle) |
Molecular weight | Theoretical: 7.729947 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: ASNNTASIAQ ARKLVEQLKM EANIDRIKVS KAAADLMAYC EAHAKEDPLL TPVPASENPF REKKFFCAIL |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.4 |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 80.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: OTHER |
Electron optics | Illumination mode: OTHER / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1320686 |
Initial angle assignment | Type: OTHER |
Final angle assignment | Type: OTHER |