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- EMDB-33229: Cryo-EM structure of the galanin-bound GALR1-miniGo complex -

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Entry
Database: EMDB / ID: EMD-33229
TitleCryo-EM structure of the galanin-bound GALR1-miniGo complex
Map datacryoEM map of the GALR1/Go/galanin complex
Sample
  • Complex: Galanin-bound Galanin receptor type 1 in complex with miniGalphao, Gbeta/gamma subunit and a single-chain variable fragment (scFv16)
    • Protein or peptide: G protein subunit alpha o1,Guanine nucleotide-binding protein G(o) subunit alpha
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Galanin
    • Protein or peptide: Galanin receptor type 1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: single Fab chain (svFv16)
KeywordsGPCR / Galanin receptor 1 / miniGo / SIGNALING PROTEIN
Function / homology
Function and homology information


galanin receptor binding / type 1 galanin receptor binding / type 2 galanin receptor binding / type 3 galanin receptor binding / galanin receptor activity / positive regulation of large conductance calcium-activated potassium channel activity / guanyl nucleotide binding / positive regulation of timing of catagen / positive regulation of cortisol secretion / regulation of glucocorticoid metabolic process ...galanin receptor binding / type 1 galanin receptor binding / type 2 galanin receptor binding / type 3 galanin receptor binding / galanin receptor activity / positive regulation of large conductance calcium-activated potassium channel activity / guanyl nucleotide binding / positive regulation of timing of catagen / positive regulation of cortisol secretion / regulation of glucocorticoid metabolic process / negative regulation of lymphocyte proliferation / mu-type opioid receptor binding / negative regulation of adenylate cyclase activity / corticotropin-releasing hormone receptor 1 binding / neuropeptide hormone activity / neuropeptide binding / G protein-coupled peptide receptor activity / feeding behavior / insulin secretion / dopamine receptor signaling pathway / peptide hormone binding / response to immobilization stress / neuropeptide signaling pathway / G protein-coupled serotonin receptor binding / protein kinase A signaling / cAMP-mediated signaling / Peptide ligand-binding receptors / secretory granule / muscle contraction / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / response to insulin / adenylate cyclase-modulating 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 activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / 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 / response to estrogen / 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 / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / phospholipase C-activating G protein-coupled receptor signaling pathway / Ca2+ pathway / G alpha (i) signalling events / positive regulation of cytosolic calcium ion concentration / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / cell population proliferation / Ras protein signal transduction / Extra-nuclear estrogen signaling / response to xenobiotic stimulus / positive regulation of apoptotic process / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / neuronal cell body / synapse / protein-containing complex binding / GTP binding / signal transduction / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular exosome / extracellular region / membrane / metal ion binding
Similarity search - Function
Galanin receptor 1 / Galanin receptor family / Galanin / Galanin precursor / Galanin message associated peptide (GMAP) / Galanin / Galanin message associated peptide (GMAP) / Galanin signature. / Galanin / G-protein alpha subunit, group I ...Galanin receptor 1 / Galanin receptor family / Galanin / Galanin precursor / Galanin message associated peptide (GMAP) / Galanin / Galanin message associated peptide (GMAP) / Galanin signature. / Galanin / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / 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. / WD domain, G-beta repeat / 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
G protein subunit alpha o1 / G protein subunit alpha o1 / Guanine nucleotide-binding protein G(o) subunit alpha / Galanin peptides / Galanin receptor type 1 / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsJiang W / Zheng S
Funding support China, 1 items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China) China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2022
Title: Structural insights into galanin receptor signaling.
Authors: Wentong Jiang / Sanduo Zheng /
Abstract: Galanin is a biologically active neuropeptide, and functions through three distinct G protein–coupled receptors (GPCRs), namely GALR1, GALR2, and GALR3. GALR signaling plays important roles in ...Galanin is a biologically active neuropeptide, and functions through three distinct G protein–coupled receptors (GPCRs), namely GALR1, GALR2, and GALR3. GALR signaling plays important roles in regulating various physiological processes such as energy metabolism, neuropathic pain, epileptic activity, and sleep homeostasis. GALR1 and GALR3 signal through the Gi/o pathway, whereas GALR2 signals mainly through the Gq/11 pathway. However, the molecular basis for galanin recognition and G protein selectivity of GALRs remains poorly understood. Here, we report the cryoelectron microscopy structures of the GALR1-Go and the GALR2-Gq complexes bound to the endogenous ligand galanin or spexin. The galanin peptide mainly adopts an alpha helical structure, which binds at the extracellular vestibule of the receptors, nearly parallel to the membrane plane without penetrating deeply into the receptor core. Structural analysis combined with functional studies reveals important structural determinants for the G protein selectivity of GALRs as well as other class A GPCRs. In addition, we show that the zinc ion is a negative allosteric regulator of GALR1 but not GALR2. Our studies provide insight into the mechanisms of G protein selectivity of GPCRs and highlight a potential function of the neuromodulator zinc ion as a modulator of GPCR signaling in the central nervous system.
History
DepositionApr 18, 2022-
Header (metadata) releaseMay 3, 2023-
Map releaseMay 3, 2023-
UpdateSep 20, 2023-
Current statusSep 20, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33229.png

Downloads & links

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Map

FileDownload / File: emd_33229.map.gz / Format: CCP4 / Size: 22.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationcryoEM map of the GALR1/Go/galanin complex
Voxel sizeX=Y=Z: 1.087 Å
Density
Contour LevelBy AUTHOR: 0.45
Minimum - Maximum-2.7800589 - 3.676722
Average (Standard dev.)0.00079644326 (±0.10187764)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions180180180
Spacing180180180
CellA=B=C: 195.66 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map of the GALR1/Go/galanin complex

Fileemd_33229_half_map_1.map
Annotationhalf map of the GALR1/Go/galanin complex
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map of the GALR1/Go/galanin complex

Fileemd_33229_half_map_2.map
Annotationhalf map of the GALR1/Go/galanin complex
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Galanin-bound Galanin receptor type 1 in complex with miniGalphao...

EntireName: Galanin-bound Galanin receptor type 1 in complex with miniGalphao, Gbeta/gamma subunit and a single-chain variable fragment (scFv16)
Components
  • Complex: Galanin-bound Galanin receptor type 1 in complex with miniGalphao, Gbeta/gamma subunit and a single-chain variable fragment (scFv16)
    • Protein or peptide: G protein subunit alpha o1,Guanine nucleotide-binding protein G(o) subunit alpha
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Galanin
    • Protein or peptide: Galanin receptor type 1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: single Fab chain (svFv16)

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Supramolecule #1: Galanin-bound Galanin receptor type 1 in complex with miniGalphao...

SupramoleculeName: Galanin-bound Galanin receptor type 1 in complex with miniGalphao, Gbeta/gamma subunit and a single-chain variable fragment (scFv16)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: G protein subunit alpha o1,Guanine nucleotide-binding protein G(o...

MacromoleculeName: G protein subunit alpha o1,Guanine nucleotide-binding protein G(o) subunit alpha
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.447115 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGCTLSAEER AALERSKAIE KNLKEDGISA AKDVKLLLLG ADNSGKSTIV KQMKIIHGGS GGSGGTTGIV ETHFTFKNLH FRLFDVGGQ RSERKKWIHC FEDVTAIIFC VDLSDYNRMH ESLMLFDSIC NNKFFIDTSI ILFLNKKDLF GEKIKKSPLT I CFPEYTGP ...String:
MGCTLSAEER AALERSKAIE KNLKEDGISA AKDVKLLLLG ADNSGKSTIV KQMKIIHGGS GGSGGTTGIV ETHFTFKNLH FRLFDVGGQ RSERKKWIHC FEDVTAIIFC VDLSDYNRMH ESLMLFDSIC NNKFFIDTSI ILFLNKKDLF GEKIKKSPLT I CFPEYTGP NTYEDAAAYI QAQFESKNRS PNKEIYCHMT CATDTNNAQV IFDAVTDIII ANNLRGCGLY

UniProtKB: G protein subunit alpha o1, G protein subunit alpha o1, Guanine nucleotide-binding protein G(o) subunit alpha

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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: 37.41693 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...String:
MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD INAICFFPNG NA FATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGV TDDGMA VATGSWDSFL KIWN

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

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Macromolecule #3: Galanin

MacromoleculeName: Galanin / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.161446 KDa
SequenceString:
GWTLNSAGYL LGPHAVGNHR SFSDKNGLTS

UniProtKB: Galanin peptides

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Macromolecule #4: Galanin receptor type 1

MacromoleculeName: Galanin receptor type 1 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.38293 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DYKDDDDKGS MELAVGNLSE GNASWPEPPA PEPGPLFGIG VENFVTLVVF GLIFALGVLG NSLVITVLAR SKPGKPRSTT NLFILNLSI ADLAYLLFCI PFQATVYALP TWVLGAFICK FIHYFFTVSM LVSIFTLAAM SVDRYVAIVH SRRSSSLRVS R NALLGVGC ...String:
DYKDDDDKGS MELAVGNLSE GNASWPEPPA PEPGPLFGIG VENFVTLVVF GLIFALGVLG NSLVITVLAR SKPGKPRSTT NLFILNLSI ADLAYLLFCI PFQATVYALP TWVLGAFICK FIHYFFTVSM LVSIFTLAAM SVDRYVAIVH SRRSSSLRVS R NALLGVGC IWALSIAMAS PVAYHQGLFH PRASNQTFCW EQWPDPRHKK AYVVCTFVFG YLLPLLLICF CYAKVLNHLH KK LKNMSKK SEASKKKTAQ TVLVVVVVFG ISWLPHHIIH LWAEFGVFPL TPASFLFRIT AHCLAYSNSS VNPIIYAFLS ENF RKAYKQ VFKCHIGGGG GGAGALEVLF Q

UniProtKB: Galanin receptor type 1

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Macromolecule #5: 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: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.845078 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFSAI L

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

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Macromolecule #6: single Fab chain (svFv16)

MacromoleculeName: single Fab chain (svFv16) / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 31.857369 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: PDVQLVESGG GLVQPGGSRK LSCSASGFAF SSFGMHWVRQ APEKGLEWVA YISSGSGTIY YADTVKGRFT ISRDDPKNTL FLQMTSLRS EDTAMYYCVR SIYYYGSSPF DFWGQGTTLT VSSGGGGSGG GGSGGGGSDI VMTQATSSVP VTPGESVSIS C RSSKSLLH ...String:
PDVQLVESGG GLVQPGGSRK LSCSASGFAF SSFGMHWVRQ APEKGLEWVA YISSGSGTIY YADTVKGRFT ISRDDPKNTL FLQMTSLRS EDTAMYYCVR SIYYYGSSPF DFWGQGTTLT VSSGGGGSGG GGSGGGGSDI VMTQATSSVP VTPGESVSIS C RSSKSLLH SNGNTYLYWF LQRPGQSPQL LIYRMSNLAS GVPDRFSGSG SGTAFTLTIS RLEAEDVGVY YCMQHLEYPL TF GAGTKLE LKAAAGAPLE VLFQGPGAWS HPQFEKGAED QVDPRLIDGK GAAHHHHHHH H

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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

Concentration5.1 mg/mL
BufferpH: 7.4
Component:
ConcentrationName
25.0 mMHEPEs
150.0 mMNaClSodium chloride
0.01 g/100mlLMNG
100.0 nMGalanin
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 40 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 101.325 kPa
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 281.15 K

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 426045

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT
Output model

PDB-7xjj:
Cryo-EM structure of the galanin-bound GALR1-miniGo complex

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