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- PDB-7e14: Compound2_GLP-1R_OWL833_Gs complex structure -

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Basic information

Entry
Database: PDB / ID: 7.0E+14
TitleCompound2_GLP-1R_OWL833_Gs complex structure
Components
  • G protein
  • Glucagon-like peptide 1 receptor
  • Gs
  • Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
  • Nb35
KeywordsMEMBRANE PROTEIN / ago-allosteric modulation of GLP-1R
Function / homology
Function and homology information


glucagon-like peptide 1 receptor activity / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / glucagon receptor activity / positive regulation of blood pressure / Activation of the phototransduction cascade / hormone secretion / post-translational protein targeting to membrane, translocation / Activation of G protein gated Potassium channels ...glucagon-like peptide 1 receptor activity / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / glucagon receptor activity / positive regulation of blood pressure / Activation of the phototransduction cascade / hormone secretion / post-translational protein targeting to membrane, translocation / 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 / G alpha (12/13) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Ca2+ pathway / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / G alpha (q) signalling events / response to psychosocial stress / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / regulation of heart contraction / peptide hormone binding / activation of adenylate cyclase activity / negative regulation of blood pressure / adenylate cyclase-activating G protein-coupled receptor signaling pathway / photoreceptor disc membrane / Glucagon-type ligand receptors / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / transmembrane signaling receptor activity / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / sensory perception of taste / signaling receptor complex adaptor activity / retina development in camera-type eye / positive regulation of cytosolic calcium ion concentration / GTPase binding / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / learning or memory / cell surface receptor signaling pathway / cell population proliferation / G protein-coupled receptor signaling pathway / GTPase activity / synapse / protein-containing complex binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
GPCR, family 2, extracellular hormone receptor domain / Hormone receptor fold / GPCR, family 2, glucagon-like peptide-1 receptor / : / GPCR, family 2, glucagon-like peptide-1/glucagon 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 ...GPCR, family 2, extracellular hormone receptor domain / Hormone receptor fold / GPCR, family 2, glucagon-like peptide-1 receptor / : / GPCR, family 2, glucagon-like peptide-1/glucagon 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. / Rhopdopsin 7-helix transmembrane proteins / Rhodopsin 7-helix transmembrane proteins / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Few Secondary Structures / Irregular / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein beta WD-40 repeat / P-loop containing nucleotide triphosphate hydrolases / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Immunoglobulins / Up-down Bundle / Immunoglobulin-like / Sandwich / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
CHOLESTEROL / N-tert-butyl-6,7-bis(chloranyl)quinoxalin-2-amine / Chem-V6G / Glucagon-like peptide 1 receptor / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Bos taurus (domestic cattle)
Rattus norvegicus (Norway rat)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsCong, Z.T. / Chen, L.N. / Ma, H.L. / Yang, D.H. / Xu, H.E. / Zhang, Y. / Wang, M.W.
CitationJournal: Nat Commun / Year: 2021
Title: Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor.
Authors: Zhaotong Cong / Li-Nan Chen / Honglei Ma / Qingtong Zhou / Xinyu Zou / Chenyu Ye / Antao Dai / Qing Liu / Wei Huang / Xianqiang Sun / Xi Wang / Peiyu Xu / Lihua Zhao / Tian Xia / Wenge Zhong ...Authors: Zhaotong Cong / Li-Nan Chen / Honglei Ma / Qingtong Zhou / Xinyu Zou / Chenyu Ye / Antao Dai / Qing Liu / Wei Huang / Xianqiang Sun / Xi Wang / Peiyu Xu / Lihua Zhao / Tian Xia / Wenge Zhong / Dehua Yang / H Eric Xu / Yan Zhang / Ming-Wei Wang /
Abstract: The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy ...The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric G. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics.
History
DepositionJan 30, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 7, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
A: Gs
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: G protein
N: Nb35
R: Glucagon-like peptide 1 receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)142,59912
Polymers139,5135
Non-polymers3,0867
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area15810 Å2
ΔGint-59 kcal/mol
Surface area49280 Å2

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Components

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Protein , 4 types, 4 molecules ABGR

#1: Protein Gs


Mass: 28989.904 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human)
Production host: Insect cell expression vector pTIE1 (others)
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37915.496 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: GNB1
Production host: Insect cell expression vector pTIE1 (others)
References: UniProt: P62871
#3: Protein G protein


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat)
Production host: Insect cell expression vector pTIE1 (others)
#5: Protein Glucagon-like peptide 1 receptor / GLP-1R


Mass: 50860.801 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GLP1R
Production host: Insect cell expression vector pTIE1 (others)
References: UniProt: P43220

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Antibody , 1 types, 1 molecules N

#4: Antibody Nb35


Mass: 13885.439 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others)
Production host: Insect cell expression vector pTIE1 (others)

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Non-polymers , 3 types, 7 molecules

#6: Chemical ChemComp-V6G / 3-[(1S,2S)-1-(5-[(4S)-2,2-dimethyloxan-4-yl]-2-{(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-4-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carbonyl}-1H-indol-1-yl)-2-methylcyclopropyl]-1,2,4-oxadiazol-5(4H)-one


Mass: 882.956 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C48H48F2N10O5 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C27H46O
#8: Chemical ChemComp-HNO / N-tert-butyl-6,7-bis(chloranyl)quinoxalin-2-amine


Mass: 270.158 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H13Cl2N3

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Details

Has ligand of interestY

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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

Component
IDNameTypeEntity IDParent-IDSource
1compound2_GLP1R_OWL833_Gs-complexCOMPLEX#1-#50MULTIPLE SOURCES
2GsCOMPLEX#11RECOMBINANT
3Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1COMPLEX#21RECOMBINANT
4G proteinCOMPLEX#31RECOMBINANT
5Nb35COMPLEX#41RECOMBINANT
6Glucagon-like peptide 1 receptorCOMPLEX#51RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Bos taurus (domestic cattle)9913
43Rattus norvegicus (Norway rat)10166
54synthetic construct (others)32630
65Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Insect cell expression vector pTIE1 (others)266783
32Insect cell expression vector pTIE1 (others)266783
43Insect cell expression vector pTIE1 (others)266783
54Insect cell expression vector pTIE1 (others)266783
65Insect cell expression vector pTIE1 (others)266783
Buffer solutionpH: 7.5
SpecimenConc.: 10 mg/ml / Embedding 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: FIELD EMISSION GUN / 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: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 345411 / Symmetry type: POINT

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