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- EMDB-33230: Cryo-EM structure of the galanin-bound GALR2-miniGq complex -

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Basic information

Entry
Database: EMDB / ID: EMD-33230
TitleCryo-EM structure of the galanin-bound GALR2-miniGq complex
Map data
Sample
  • Complex: Galanin-bound Galanin receptor 2 in complex with Galphaq, Gbeta/gamma subunit and single chain variable fragment (scFv16)
    • Protein or peptide: Galanin
    • Protein or peptide: Guanine nucleotide-binding protein G(q)
    • 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: single Fab chain (svFv16)
    • Protein or peptide: Galanin receptor type 2
Function / homology
Function and homology information


galanin-activated signaling pathway / 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 / positive regulation of timing of catagen / positive regulation of cortisol secretion / regulation of glucocorticoid metabolic process ...galanin-activated signaling pathway / 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 / positive regulation of timing of catagen / positive regulation of cortisol secretion / regulation of glucocorticoid metabolic process / inositol phosphate metabolic process / negative regulation of lymphocyte proliferation / phosphatidylinositol metabolic process / neuropeptide hormone activity / neuropeptide binding / feeding behavior / insulin secretion / peptide hormone binding / cAMP-mediated signaling / response to immobilization stress / neuropeptide signaling pathway / protein kinase A signaling / Peptide ligand-binding receptors / muscle contraction / secretory granule / Olfactory Signaling Pathway / Activation of the phototransduction cascade / response to insulin / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / 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 / cilium / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / 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 / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / response to estrogen / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / neuron projection development / 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 / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling 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 / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / learning or memory / cell surface receptor signaling pathway / 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 / signal transduction / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular exosome / extracellular region / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Galanin receptor 2 / Galanin receptor family / Galanin / Galanin precursor / Galanin message associated peptide (GMAP) / Galanin / Galanin message associated peptide (GMAP) / Galanin signature. / Galanin / Serpentine type 7TM GPCR chemoreceptor Srsx ...Galanin receptor 2 / Galanin receptor family / Galanin / Galanin precursor / Galanin message associated peptide (GMAP) / Galanin / Galanin message associated peptide (GMAP) / Galanin signature. / Galanin / Serpentine type 7TM GPCR chemoreceptor Srsx / 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. / 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
Galanin receptor type 2 / Galanin peptides / 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) releaseJun 29, 2022-
Map releaseJun 29, 2022-
UpdateJun 29, 2022-
Current statusJun 29, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33230.png

Downloads & links

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Map

FileDownload / File: emd_33230.map.gz / Format: CCP4 / Size: 22.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.087 Å
Density
Contour LevelBy AUTHOR: 0.45
Minimum - Maximum-2.597051 - 4.5098243
Average (Standard dev.)0.00017140423 (±0.11523314)
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: #1

Fileemd_33230_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_33230_half_map_2.map
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 2 in complex with Galphaq, Gbeta/g...

EntireName: Galanin-bound Galanin receptor 2 in complex with Galphaq, Gbeta/gamma subunit and single chain variable fragment (scFv16)
Components
  • Complex: Galanin-bound Galanin receptor 2 in complex with Galphaq, Gbeta/gamma subunit and single chain variable fragment (scFv16)
    • Protein or peptide: Galanin
    • Protein or peptide: Guanine nucleotide-binding protein G(q)
    • 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: single Fab chain (svFv16)
    • Protein or peptide: Galanin receptor type 2

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Supramolecule #1: Galanin-bound Galanin receptor 2 in complex with Galphaq, Gbeta/g...

SupramoleculeName: Galanin-bound Galanin receptor 2 in complex with Galphaq, Gbeta/gamma subunit and single chain variable fragment (scFv16)
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens, synthetic construct

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Macromolecule #1: Galanin

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

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Macromolecule #2: Guanine nucleotide-binding protein G(q)

MacromoleculeName: Guanine nucleotide-binding protein G(q) / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.026797 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA ...String:
MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA RYTTPEAATP EPGDDPRVTR AKYFIRKEFV DISTASGDGR HICYPHFTCA VDTENARRIF NDCKDIILQM NL REYNLV

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Macromolecule #3: 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: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.389934 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: HHHHHHGSMS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLVS ASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG HTGYLSCCRF L DDNQIVTS ...String:
HHHHHHGSMS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLVS ASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG HTGYLSCCRF L DDNQIVTS SGDTTCALWD IETGQQTTTF TGHTGDVMSL SLAPDTRLFV SGACDASAKL WDVREGMCRQ TFTGHESDIN AI CFFPNGN AFATGSDDAT CRLFDLRADQ ELMTYSHDNI ICGITSVSFS KSGRLLLAGY DDFNCNVWDA LKADRAGVLA GHD NRVSCL GVTDDGMAVA TGSWDSFLKI WN

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Macromolecule #4: 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: 4 / 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

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Macromolecule #5: single Fab chain (svFv16)

MacromoleculeName: single Fab chain (svFv16) / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 32.071615 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GRPDVQLVES GGGLVQPGGS RKLSCSASGF AFSSFGMHWV RQAPEKGLEW VAYISSGSGT IYYADTVKGR FTISRDDPKN TLFLQMTSL RSEDTAMYYC VRSIYYYGSS PFDFWGQGTT LTVSSGGGGS GGGGSGGGGS DIVMTQATSS VPVTPGESVS I SCRSSKSL ...String:
GRPDVQLVES GGGLVQPGGS RKLSCSASGF AFSSFGMHWV RQAPEKGLEW VAYISSGSGT IYYADTVKGR FTISRDDPKN TLFLQMTSL RSEDTAMYYC VRSIYYYGSS PFDFWGQGTT LTVSSGGGGS GGGGSGGGGS DIVMTQATSS VPVTPGESVS I SCRSSKSL LHSNGNTYLY WFLQRPGQSP QLLIYRMSNL ASGVPDRFSG SGSGTAFTLT ISRLEAEDVG VYYCMQHLEY PL TFGAGTK LELKAAAGAP LEVLFQGPGA WSHPQFEKGA EDQVDPRLID GKGAAHHHHH HHH

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Macromolecule #6: Galanin receptor type 2

MacromoleculeName: Galanin receptor type 2 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 36.401867 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DYKDDDDKGS MNVSGCPGAG NASQAGGGGG WHPEAVIVPL LFALIFLVGT VGNTLVLAVL LRGGQAVSTT NLFILNLGVA DLCFILCCV PFQATIYTLD GWVFGSLLCK AVHFLIFLTM HASSFTLAAV SLDRYLAIRY PLHSRELRTP RNALAAIGLI W GLSLLFSG ...String:
DYKDDDDKGS MNVSGCPGAG NASQAGGGGG WHPEAVIVPL LFALIFLVGT VGNTLVLAVL LRGGQAVSTT NLFILNLGVA DLCFILCCV PFQATIYTLD GWVFGSLLCK AVHFLIFLTM HASSFTLAAV SLDRYLAIRY PLHSRELRTP RNALAAIGLI W GLSLLFSG PYLSYYQQSQ LANLTVCHPA WSAPRRRAMD ICTFVFSYLL PVLVLGLTYA RTLRYLWRAV DPVAAGSGAR RA KRKVTRM ILIVAALFCL CWMPHHALIL CVWFGQFPLT RATYALRILS HLVSYANSCV NPIVYALVSK HFRKGFRTIC AGL LGRAGS LEVLFQ

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation state3D array

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Sample preparation

Concentration5.6 mg/mL
BufferpH: 7.4
Component:
ConcentrationName
25.0 mMHEPEs
150.0 nMNaClSodium chloride
0.01 g/100mlLMNG
100.0 nMgalanin
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 101.325 kPa
VitrificationCryogen name: ETHANE

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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: 2.3000000000000003 µm / Nominal defocus min: 1.2 µm
Sample stageCooling holder cryogen: NITROGEN
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

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: 571842

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-7xjk:
Cryo-EM structure of the galanin-bound GALR2-miniGq complex

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