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- EMDB-39631: Cryo-EM structure of GLP1 complex bound with Retatrutide -

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Basic information

Entry
Database: EMDB / ID: EMD-39631
TitleCryo-EM structure of GLP1 complex bound with Retatrutide
Map data
Sample
  • Complex: GLP1 complex
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
    • 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: NB35
    • Protein or peptide: Retatrutide
    • Protein or peptide: Glucagon-like peptide 1 receptor
  • Ligand: 20-[[(2~{S})-1-oxidanyl-1,5-bis(oxidanylidene)-5-[2-[2-(2-oxidanylideneethoxy)ethoxy]ethylamino]pentan-2-yl]amino]-20-oxidanylidene-icosanoic acid
KeywordsGLP1 / Retatrutide / MEMBRANE PROTEIN
Function / homology
Function and homology information


glucagon-like peptide 1 receptor activity / glucagon receptor activity / positive regulation of blood pressure / hormone secretion / post-translational protein targeting to membrane, translocation / response to psychosocial stress / regulation of heart contraction / peptide hormone binding / PKA activation in glucagon signalling / developmental growth ...glucagon-like peptide 1 receptor activity / glucagon receptor activity / positive regulation of blood pressure / hormone secretion / post-translational protein targeting to membrane, translocation / response to psychosocial stress / regulation of heart contraction / peptide hormone binding / PKA activation in glucagon signalling / developmental growth / hair follicle placode formation / D1 dopamine receptor binding / intracellular transport / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / activation of adenylate cyclase activity / adenylate cyclase inhibitor activity / Hedgehog 'off' state / positive regulation of protein localization to cell cortex / negative regulation of blood pressure / T cell migration / Adenylate cyclase inhibitory pathway / adenylate cyclase-activating adrenergic receptor signaling pathway / D2 dopamine receptor binding / response to prostaglandin E / adenylate cyclase regulator activity / G protein-coupled serotonin receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / cellular response to glucagon stimulus / regulation of insulin secretion / cellular response to forskolin / regulation of mitotic spindle organization / adenylate cyclase activator activity / trans-Golgi network membrane / Regulation of insulin secretion / negative regulation of inflammatory response to antigenic stimulus / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / G protein-coupled receptor binding / response to peptide hormone / bone development / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / platelet aggregation / G-protein beta/gamma-subunit complex binding / centriolar satellite / cognition / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / GDP binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / sensory perception of smell / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / transmembrane signaling receptor activity / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / positive regulation of cold-induced thermogenesis / retina development in camera-type eye / G protein activity / positive regulation of cytosolic calcium ion concentration / GTPase binding / Ca2+ pathway / fibroblast proliferation / midbody / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / cell cortex / G alpha (i) signalling events
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 alpha subunit, group S / G-protein alpha subunit, group I / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / 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 / G protein beta WD-40 repeat protein / 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. / 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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Glucagon-like peptide 1 receptor / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.74 Å
AuthorsZhao L / Xu HE / Yuan Q
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: To Be Published
Title: Cryo-EM structure of GLP1 complex bound with Retatrutide
Authors: Zhao L / Xu HE / Yuan Q
History
DepositionMar 31, 2024-
Header (metadata) releaseApr 16, 2025-
Map releaseApr 16, 2025-
UpdateApr 16, 2025-
Current statusApr 16, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_39631.png

Downloads & links

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Map

FileDownload / File: emd_39631.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
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

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.73 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.36
Minimum - Maximum-1.7129828 - 2.940257
Average (Standard dev.)0.001470903 (±0.061379284)
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_39631_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_39631_half_map_2.map
Projections & Slices
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Sample components

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Entire : GLP1 complex

EntireName: GLP1 complex
Components
  • Complex: GLP1 complex
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
    • 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: NB35
    • Protein or peptide: Retatrutide
    • Protein or peptide: Glucagon-like peptide 1 receptor
  • Ligand: 20-[[(2~{S})-1-oxidanyl-1,5-bis(oxidanylidene)-5-[2-[2-(2-oxidanylideneethoxy)ethoxy]ethylamino]pentan-2-yl]amino]-20-oxidanylidene-icosanoic acid

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Supramolecule #1: GLP1 complex

SupramoleculeName: GLP1 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine n...

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
EC number: Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.879465 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
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

UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(i) subunit alpha-1, ...UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short

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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: Homo sapiens (human)
Molecular weightTheoretical: 43.299262 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: HHHHSSGLVP RGSHMASHHH HHHHHHHGSL LQSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKI YAMHWGTDSR LLVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT R EGNVRVSR ...String:
HHHHSSGLVP RGSHMASHHH HHHHHHHGSL LQSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKI YAMHWGTDSR LLVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT R EGNVRVSR ELAGHTGYLS CCRFLDDNQI VTSSGDTTCA LWDIETGQQT TTFTGHTGDV MSLSLAPDTR LFVSGACDAS AK LWDVREG MCRQTFTGHE SDINAICFFP NGNAFATGSD DATCRLFDLR ADQELMTYSH DNIICGITSV SFSKSGRLLL AGY DDFNCN VWDALKADRA GVLAGHDNRV SCLGVTDDGM AVATGSWDSF LKIWNGSSGG GGSGGGGSSG VSGWRLFKKI S

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: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
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: NB35

MacromoleculeName: NB35 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.364009 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MAQVQLQESG GGLVQPGGSL RLSCAASGFT FSNYKMNWVR QAPGKGLEWV SDISQSGASI SYTGSVKGRF TISRDNAKNT LYLQMNSLK PEDTAVYYCA RCPAPFTRDC FDVTSTTYAY RGQGTQVTVS SHH

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Macromolecule #5: Retatrutide

MacromoleculeName: Retatrutide / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.629031 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
Y(AIB)QGTFTSDY SI(2ML)LDKKAQ(AIB) AFIEYLLEGG PSS

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Macromolecule #6: Glucagon-like peptide 1 receptor

MacromoleculeName: Glucagon-like peptide 1 receptor / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50.860801 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
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 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

UniProtKB: Glucagon-like peptide 1 receptor

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Macromolecule #7: 20-[[(2~{S})-1-oxidanyl-1,5-bis(oxidanylidene)-5-[2-[2-(2-oxidany...

MacromoleculeName: 20-[[(2~{S})-1-oxidanyl-1,5-bis(oxidanylidene)-5-[2-[2-(2-oxidanylideneethoxy)ethoxy]ethylamino]pentan-2-yl]amino]-20-oxidanylidene-icosanoic acid
type: ligand / ID: 7 / Number of copies: 1 / Formula: A1D7Q
Molecular weightTheoretical: 616.784 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: 7.04
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: LAB6
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 18.0 µm / Nominal defocus min: 8.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.74 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 168975
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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