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- EMDB-67036: Glucagon-like peptide 1 receptor-Gs complex activated by the smal... -

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Entry
Database: EMDB / ID: EMD-67036
TitleGlucagon-like peptide 1 receptor-Gs complex activated by the small molecule agonist SIM1
Map data
Sample
  • Complex: Glucagon-like peptide-1 receptor-Gs complex activated by the small molecule agonist SIM1
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Nanobody 35
    • Protein or peptide: Glucagon-like peptide 1 receptor
  • Ligand: 1-[3,5-dimethyl-4-[2-[[4-oxidanylidene-2-[4-(trifluoromethyloxy)phenyl]-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]phenyl]pyrrolidine-2,5-dione
KeywordsSmall molecule agonist / complex / GLP-1R / MEMBRANE PROTEIN / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


glucagon-like peptide 1 receptor activity / glucagon receptor activity / 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 ...glucagon-like peptide 1 receptor activity / glucagon receptor activity / 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 / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / G alpha (i) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / regulation of heart contraction / 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 / G alpha (z) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / Extra-nuclear estrogen signaling / G alpha (q) signalling events / G alpha (s) signalling events / response to psychosocial stress / photoreceptor outer segment membrane / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / spectrin binding / G alpha (i) signalling events / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / sensory perception of taste / alkylglycerophosphoethanolamine phosphodiesterase activity / retina development in camera-type eye / peptide hormone binding / cardiac muscle cell apoptotic process / photoreceptor outer segment / activation of adenylate cyclase activity / photoreceptor inner segment / cell population proliferation / phospholipase C-activating G protein-coupled receptor signaling pathway / transmembrane signaling receptor activity / Glucagon-type ligand receptors / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / G-protein beta-subunit binding / positive regulation of cytosolic calcium ion concentration / adenylate cyclase-activating G protein-coupled receptor signaling pathway / signaling receptor complex adaptor activity / GTPase binding / cell body / cellular response to hypoxia / G alpha (s) signalling events / 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
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. / : / 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 ...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. / 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 WD-40 repeat protein / 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. / WD40 repeats / WD40 repeat / 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 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Similarity search - Component
Biological speciesHomo sapiens (human) / Bos taurus (domestic cattle) / Rattus norvegicus (Norway rat) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.61 Å
AuthorsXu HE / Shan H / He Q / Zhao L
Funding support China, 3 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32130022 China
National Natural Science Foundation of China (NSFC)82121005 China
National Natural Science Foundation of China (NSFC)82495184 China
CitationJournal: Acta Pharmacol Sin / Year: 2026
Title: Structural basis for small-molecule agonism at GCGR and GIPR via a conserved intracellular allosteric site.
Authors: Qian He / Hong Shan / Wen Hu / H Eric Xu / Li-Hua Zhao /
Abstract: The glucagon receptor (GCGR) and gastric inhibitory polypeptide receptor (GIPR) are class B GPCRs that regulate glucose homeostasis and energy balance, making them key targets for type 2 diabetes and ...The glucagon receptor (GCGR) and gastric inhibitory polypeptide receptor (GIPR) are class B GPCRs that regulate glucose homeostasis and energy balance, making them key targets for type 2 diabetes and obesity. Achieving preferential G signaling at these receptors with small molecules remains an unmet challenge. Here, we report SIM1, developed through optimization of the PCO371 scaffold, which exhibits preferential G signaling at GCGR and GIPR with minimal detectable β-arrestin recruitment and substantially improved efficacy at GIPR. Cryo-EM structures of SIM1-GCGR-G (2.53 Å) and SIM1-GIPR-G (2.74 Å) reveal a shared intracellular allosteric interface at the receptor-G protein coupling region, distinct from extracellular peptide recognition. Structural comparison with GLP1R suggests that intracellular conformational constraints contribute to differential SIM1 responsiveness, which is restored by targeted mutations. Guided by these insights, analogs SIM2 and SIM3 exhibited up to 20-fold enhanced potency while maintaining an apparent preferential G signaling profile. These findings reveal a conserved intracellular allosteric activation mechanism across multiple class B GPCRs and identify SIM1 and its analogs as valuable chemical tools for investigating receptor-specific intracellular allosteric regulation and G protein-preferential signaling.
History
DepositionNov 12, 2025-
Header (metadata) releaseSep 30, 2026-
Map releaseSep 30, 2026-
UpdateSep 30, 2026-
Current statusSep 30, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_67036.png

Downloads & links

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Map

FileDownload / File: emd_67036.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 360 pix.
= 262.8 Å		0.73 Å/pix.
x 360 pix.
= 262.8 Å		0.73 Å/pix.
x 360 pix.
= 262.8 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.73 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-0.001785483 - 1.6766968
Average (Standard dev.)0.000788707 (±0.019347092)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 262.80002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_67036_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_67036_half_map_2.map
Projections & Slices
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Sample components

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Entire : Glucagon-like peptide-1 receptor-Gs complex activated by the smal...

EntireName: Glucagon-like peptide-1 receptor-Gs complex activated by the small molecule agonist SIM1
Components
  • Complex: Glucagon-like peptide-1 receptor-Gs complex activated by the small molecule agonist SIM1
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Nanobody 35
    • Protein or peptide: Glucagon-like peptide 1 receptor
  • Ligand: 1-[3,5-dimethyl-4-[2-[[4-oxidanylidene-2-[4-(trifluoromethyloxy)phenyl]-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]phenyl]pyrrolidine-2,5-dione

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Supramolecule #1: Glucagon-like peptide-1 receptor-Gs complex activated by the smal...

SupramoleculeName: Glucagon-like peptide-1 receptor-Gs complex activated by the small molecule agonist SIM1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha

MacromoleculeName: Guanine nucleotide-binding protein G(s) subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 41.879465 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGCTLSAEDK AAVERSKMIE KQLQKDKQVY RATHRLLLLG ADNSGKSTIV KQMRIYHVNG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMIE KQLQKDKQVY RATHRLLLLG ADNSGKSTIV KQMRIYHVNG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTSGIFETK FQVDKVNFHM FDVGAQRDER RKWIQCFNDV TAIIFVVDSS DYNRLQEALN DF KSIWNNR WLRTISVILF LNKQDLLAEK VLAGKSKIED YFPEFARYTT PEDATPEPGE DPRVTRAKYF IRDEFLRIST ASG DGRHYC YPHFTCSVDT ENARRIFNDC RDIIQRMHLR QYELL

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: 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
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 37.915496 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: 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

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: 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
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #4: Nanobody 35

MacromoleculeName: Nanobody 35 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 14.087715 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MAQVQLQESG GGLVQPGGSL RLSCAASGFT FSNYKMNWVR QAPGKGLEWV SDISQSGASI SYTGSVKGRF TISRDNAKNT LYLQMNSLK PEDTAVYYCA RCPAPFTRDC FDVTSTTYAY RGQGTQVTVS S

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Macromolecule #5: Glucagon-like peptide 1 receptor

MacromoleculeName: Glucagon-like peptide 1 receptor / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50.894816 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: 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 YWILVEGVYL YTLLAFSVLS EQ WIFRLYV SIGWGVPLLF VVPWGIVKYL YEDEGCWTRN SNMNYWLIIR LPILFAIGVN FLIFVRVICI VVSKLKANLM CKT DIKCRL AKSTLTLIPL FGTHEVIFAF VMDEHARGTL RFIKLFTELS FTSFQGLMVA ILYCFVNNEV QLEFRKSWER WRLE HLHIQ RDSSMKPLKC PTSSLSSGAT AGSSMYTATC QASCS

UniProtKB: Glucagon-like peptide 1 receptor

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Macromolecule #6: 1-[3,5-dimethyl-4-[2-[[4-oxidanylidene-2-[4-(trifluoromethyloxy)p...

MacromoleculeName: 1-[3,5-dimethyl-4-[2-[[4-oxidanylidene-2-[4-(trifluoromethyloxy)phenyl]-1,3,8-triazaspiro[4.5]dec-1-en-8-yl]sulfonyl]ethyl]phenyl]pyrrolidine-2,5-dione
type: ligand / ID: 6 / Number of copies: 1 / Formula: A1E0Y
Molecular weightTheoretical: 606.613 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.61 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.6) / Number images used: 243636
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: PROJECTION MATCHING

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