+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-33057 | ||||||||||||||||||
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Title | Cryo-EM structure of the Boc5-bound hGLP-1R-Gs complex | ||||||||||||||||||
Map data | |||||||||||||||||||
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 / Vasopressin regulates renal water homeostasis via Aquaporins / post-translational protein targeting to membrane, translocation / 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 / photoreceptor outer segment membrane / response to psychosocial stress / regulation of heart contraction / spectrin binding / peptide hormone binding / PKA activation in glucagon signalling / hair follicle placode formation / photoreceptor outer segment / developmental growth / D1 dopamine receptor binding / intracellular transport / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / cardiac muscle cell apoptotic process / adenylate cyclase activator activity / negative regulation of blood pressure / photoreceptor inner segment / cAMP-mediated signaling / trans-Golgi network membrane / G-protein beta/gamma-subunit complex binding / bone development / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / transmembrane signaling receptor activity / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / cognition / platelet aggregation / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / 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 / 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 / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of smell / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / cellular response to hypoxia / Ca2+ pathway / positive regulation of cold-induced thermogenesis / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / G alpha (i) signalling events / cell body / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Extra-nuclear estrogen signaling / cell population proliferation / learning or memory / cell surface receptor signaling pathway / G protein-coupled receptor signaling pathway / GTPase activity Similarity search - Function | ||||||||||||||||||
Biological species | Homo sapiens (human) / Bos taurus (cattle) / Rattus norvegicus (Norway rat) / synthetic construct (others) | ||||||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.61 Å | ||||||||||||||||||
Authors | Cong ZT / Zhou QT / Li Y / Chen LN / Zhang ZC / Liang AY / Liu Q / Wu XY / Dai AT / Xia T ...Cong ZT / Zhou QT / Li Y / Chen LN / Zhang ZC / Liang AY / Liu Q / Wu XY / Dai AT / Xia T / Wu W / Zhang Y / Yang DH / Wang MW | ||||||||||||||||||
Funding support | China, 5 items
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Citation | Journal: Proc Natl Acad Sci U S A / Year: 2022 Title: Structural basis of peptidomimetic agonism revealed by small- molecule GLP-1R agonists Boc5 and WB4-24. Authors: Zhaotong Cong / Qingtong Zhou / Yang Li / Li-Nan Chen / Zi-Chen Zhang / Anyi Liang / Qing Liu / Xiaoyan Wu / Antao Dai / Tian Xia / Wei Wu / Yan Zhang / Dehua Yang / Ming-Wei Wang / Abstract: Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective in treating type 2 diabetes and obesity with proven cardiovascular benefits. However, most of these agonists are peptides and require ...Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective in treating type 2 diabetes and obesity with proven cardiovascular benefits. However, most of these agonists are peptides and require subcutaneous injection except for orally available semaglutide. Boc5 was identified as the first orthosteric nonpeptidic agonist of GLP-1R that mimics a broad spectrum of bioactivities of GLP-1 in vitro and in vivo. Here, we report the cryoelectron microscopy structures of Boc5 and its analog WB4-24 in complex with the human GLP-1R and Gs protein. Bound to the extracellular domain, extracellular loop 2, and transmembrane (TM) helices 1, 2, 3, and 7, one arm of both compounds was inserted deeply into the bottom of the orthosteric binding pocket that is usually accessible by peptidic agonists, thereby partially overlapping with the residues A8 to D15 in GLP-1. The other three arms, meanwhile, extended to the TM1-TM7, TM1-TM2, and TM2-TM3 clefts, showing an interaction feature substantially similar to the previously known small-molecule agonist LY3502970. Such a unique binding mode creates a distinct conformation that confers both peptidomimetic agonism and biased signaling induced by nonpeptidic modulators at GLP-1R. Further, the conformational difference between Boc5 and WB4-24, two closed related compounds, provides a structural framework for fine-tuning of pharmacological efficacy in the development of future small-molecule therapeutics targeting GLP-1R. | ||||||||||||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_33057.map.gz | 59.8 MB | EMDB map data format | |
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Header (meta data) | emd-33057-v30.xml emd-33057.xml | 17 KB 17 KB | Display Display | EMDB header |
Images | emd_33057.png | 43 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-33057 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-33057 | HTTPS FTP |
-Validation report
Summary document | emd_33057_validation.pdf.gz | 428.6 KB | Display | EMDB validaton report |
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Full document | emd_33057_full_validation.pdf.gz | 428.1 KB | Display | |
Data in XML | emd_33057_validation.xml.gz | 6.3 KB | Display | |
Data in CIF | emd_33057_validation.cif.gz | 7.1 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-33057 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-33057 | HTTPS FTP |
-Related structure data
Related structure data | 7x8rMC 7x8sC 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_33057.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.071 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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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 Boc5 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 Boc5 and G protein type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#5 |
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Source (natural) | Organism: Homo sapiens (human) |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
-Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Macromolecule | Name: 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: Bos taurus (cattle) |
Molecular weight | Theoretical: 45.683434 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE ...String: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE YQLIDCAQYF LDKIDVIKQA DYVPSDQDLL RCRVLTSGIF ETKFQVDKVN FHMFDVGAQR DERRKWIQCF ND VTAIIFV VASSSYNMVI REDNQTNRLQ AALKLFDSIW NNKWLRDTSV ILFLNKQDLL AEKVLAGKSK IEDYFPEFAR YTT PEDATP EPGEDPRVTR AKYFIRDEFL RISTASGDGR HYCYPHFTCA VDTENIRRVF NDCRDIIQRM HLRQYELL |
-Macromolecule #2: 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: 2 / 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 #3: 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: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 7.729947 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: ASNNTASIAQ ARKLVEQLKM EANIDRIKVS KAAADLMAYC EAHAKEDPLL TPVPASENPF REKKFFCAIL |
-Macromolecule #4: Nanobody 35
Macromolecule | Name: Nanobody 35 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: synthetic construct (others) |
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 #5: Glucagon-like peptide 1 receptor
Macromolecule | Name: Glucagon-like peptide 1 receptor / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 50.894816 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 YTLLAFSVFS 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 #6: 2,4-bis(3-methoxy-4-thiophen-2-ylcarbonyloxy-phenyl)-1,3-bis[[4-[...
Macromolecule | Name: 2,4-bis(3-methoxy-4-thiophen-2-ylcarbonyloxy-phenyl)-1,3-bis[[4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]carbonylamino]cyclobutane-1,3-dicarboxylic acid type: ligand / ID: 6 / Number of copies: 1 / Formula: BYI |
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Molecular weight | Theoretical: 1.077138 KDa |
Chemical component information | ChemComp-BYI: |
-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 / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm |
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: 2.61 Å / Resolution method: DIFFRACTION PATTERN/LAYERLINES / Number images used: 125391 |
Initial angle assignment | Type: OTHER |
Final angle assignment | Type: OTHER |