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- EMDB-30936: Molecular insights into ago-allosteric modulation of the human gl... -

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Basic information

Entry
Database: EMDB / ID: EMD-30936
TitleMolecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor
Map data
Sample
  • Complex: compound2_GLP1R_OWL833_Gs-complex
    • Other: compound2_GLP1R_OWL833_Gs-complex
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 / hormone secretion / Activation of the phototransduction cascade / positive regulation of blood pressure / 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 / hormone secretion / Activation of the phototransduction cascade / positive regulation of blood pressure / 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 / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / regulation of heart contraction / 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 / Vasopressin regulates renal water homeostasis via Aquaporins / peptide hormone binding / cAMP-mediated signaling / 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 / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / sensory perception of taste / heterotrimeric G-protein complex / transmembrane signaling receptor activity / signaling receptor complex adaptor activity / retina development in camera-type eye / GTPase binding / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / G alpha (s) signalling events / cell population proliferation / cell surface receptor signaling pathway / learning or memory / G protein-coupled receptor signaling pathway / GTPase activity / protein-containing complex binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
: / 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. / Hormone receptor domain / 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 superfamily / G-protein coupled receptors family 2 signature 2. ...: / 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. / Hormone receptor domain / 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 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. / 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. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsCong ZT / Chen LN / Ma HL / Zhou QT / Yang DH / Xu HE / Zhang Y / Wang MW
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 28, 2021-
Header (metadata) releaseJul 7, 2021-
Map releaseJul 7, 2021-
UpdateJul 7, 2021-
Current statusJul 7, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7e14
  • Surface level: 0.025
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30936.png

Downloads & links

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Map

FileDownload / File: emd_30936.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.045 Å
Density
Contour LevelBy AUTHOR: 0.02 / Movie #1: 0.025
Minimum - Maximum-0.15685889 - 0.254225
Average (Standard dev.)-0.00012619181 (±0.007669873)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 208.99998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0451.0451.045
M x/y/z200200200
origin x/y/z0.0000.0000.000
length x/y/z209.000209.000209.000
α/β/γ90.00090.00090.000
start NX/NY/NZ-210-210-210
NX/NY/NZ420420420
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS200200200
D min/max/mean-0.1570.254-0.000

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Supplemental data

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Sample components

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Entire : compound2_GLP1R_OWL833_Gs-complex

EntireName: compound2_GLP1R_OWL833_Gs-complex
Components
  • Complex: compound2_GLP1R_OWL833_Gs-complex
    • Other: compound2_GLP1R_OWL833_Gs-complex

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Supramolecule #1: compound2_GLP1R_OWL833_Gs-complex

SupramoleculeName: compound2_GLP1R_OWL833_Gs-complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Insect cell expression vector pTIE1 (others)

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Macromolecule #1: compound2_GLP1R_OWL833_Gs-complex

MacromoleculeName: compound2_GLP1R_OWL833_Gs-complex / type: other / ID: 1 / Classification: other
Source (natural)Organism: Homo sapiens (human)
SequenceString: RPQGATVSLW ETVQKWREYR RQCQRSLTED PPPATDLFCN RTFDEYACWP DGEPGSFVNV SCPWYLPWAS SVPQGHVYRF CTAEGLWLQK DNSSLPWRDL SECEESKRGE RSSPEEQLLF LYIIYTVGYA LSFSALVIAS AILLGFRHLH CTRNYIHLNL FASFILRALS ...String:
RPQGATVSLW ETVQKWREYR RQCQRSLTED PPPATDLFCN RTFDEYACWP DGEPGSFVNV SCPWYLPWAS SVPQGHVYRF CTAEGLWLQK DNSSLPWRDL SECEESKRGE RSSPEEQLLF LYIIYTVGYA LSFSALVIAS AILLGFRHLH CTRNYIHLNL FASFILRALS VFIKDAALKW MYSTAAQQHQ WDGLLSYQDS LSCRLVFLLM QYCVAANYYW LLVEGVYLYT LLAFSVLSEQ WIFRLYVSIG WGVPLLFVVP WGIVKYLYED EGCWTRNSNM NYWLIIRLPI LFAIGVNFLI FVRVICIVVS KLKANLMCKT DIKCRLAKST LTLIPLLGTH EVIFAFVMDE HARGTLRFIK LFTELSFTSF QGLMVAILYC FVNNEVQLEF RKSWERWRLE HLHIQRDSSM KPLKCPTSSL SSGATAGSSM YTATCQASCS MGCLGNSKT EDQRNEEKAQ REANKKIEKQ LQKDKQVYRA THRLLLLGAD NSGKSTIVKQ MRIYHVNSGI FETKFQVDKV NFHMFDVGAQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ AALKLFDSIW NNKWLRDTSV ILFLNKQDLL AEKVLAGKSK IEDYFPEFAR YTTPEDATPE PGEDPRVTRA KYFIRDEFLR ISTASGDGRH YCYPHFTCSV DTENIRRVFN DCRDIIQRMH LRQYELL MG SLLQSELDQL RQEAEQLKNQ IRDARKACAD ATLSQITNNI DPVGRIQMRT RRTLRGHLAK IYAMHWGTDS RLLVSASQDG KLIIWDSYTT NKVHAIPLRS SWVMTCAYAP SGNYVACGGL DNICSIYNLK TREGNVRVSR ELAGHTGYLS CCRFLDDNQI VTSSGDTTCA LWDIETGQQT TTFTGHTGDV MSLSLAPDTR LFVSGACDAS AKLWDVREGM CRQTFTGHES DINAICFFPN GNAFATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGVTDDGMAV ATGSWDSFLK IWN MASNNT ASIAQARKLV EQLKMEANID RIKVSKAAAD LMAYCEAHAK EDPLLTPVPA SENPFREKKF FCAIL QVQL QESGGGLVQP GGSLRLSCAA SGFTFSNYKM NWVRQAPGKG LEWVSDISQS GASISYTGSV KGRFTISRDN AKNTLYLQMN SLKPEDTAVY YCARCPAPFT RDCFDVTSTT YAYRGQGTQV TVSS
Recombinant expressionOrganism: Insect cell expression vector pTIE1 (others)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statecell

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Sample preparation

Concentration10 mg/mL
BufferpH: 7.5
GridModel: Quantifoil / Material: GOLD / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 101.325 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: OTHER / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 80.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 5552 / Details: previous 3D model facilitated particel picking
CTF correctionSoftware - Name: RELION (ver. 3.0.84)
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.0.84)
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 345411
DetailsDose-fractionated image stacks were subjected to beam-induced motion correction using MotionCor2.1
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6b3j


Chain - Chain ID: R
RefinementProtocol: AB INITIO MODEL / Target criteria: Correlation coefficient
Output model

PDB-7e14:
Compound2_GLP-1R_OWL833_Gs complex structure

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