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- EMDB-37944: Structure of 26RFa-pyroglutamylated RFamide peptide receptor complex -

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Entry
Database: EMDB / ID: EMD-37944
TitleStructure of 26RFa-pyroglutamylated RFamide peptide receptor complex
Map data
Sample
  • Complex: Structure of 26RFa-pyroglutamylated RFamide peptide receptor-G protein complex
    • Protein or peptide: G-alpha q
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: scFV16
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Orexigenic neuropeptide QRFP
    • Protein or peptide: Pyroglutamylated RF-amide peptide receptor
KeywordsGPCR / 26RFa / GPR103 / pyroglutamylated RFamide peptide / MEMBRANE PROTEIN
Function / homology
Function and homology information


orexigenic neuropeptide QRFP receptor binding / Orexin and neuropeptides FF and QRFP bind to their respective receptors / neuropeptide Y receptor activity / Orexin and neuropeptides FF and QRFP bind to their respective receptors / G alpha (q) signalling events / regulation of feeding behavior / grooming behavior / positive regulation of blood pressure / G-protein activation / Activation of the phototransduction cascade ...orexigenic neuropeptide QRFP receptor binding / Orexin and neuropeptides FF and QRFP bind to their respective receptors / neuropeptide Y receptor activity / Orexin and neuropeptides FF and QRFP bind to their respective receptors / G alpha (q) signalling events / regulation of feeding behavior / grooming behavior / 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 / neuropeptide hormone activity / 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 / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / 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) / 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 / alkylglycerophosphoethanolamine phosphodiesterase activity / 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 / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / G alpha (q) signalling events / photoreceptor outer segment membrane / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / photoreceptor outer segment / neuropeptide signaling pathway / cellular response to hormone stimulus / cardiac muscle cell apoptotic process / photoreceptor inner segment / locomotory behavior / G protein-coupled receptor activity / peptide binding / cellular response to catecholamine stimulus / sensory perception of taste / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / GTPase binding / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / cell body / positive regulation of cytosolic calcium ion concentration / cellular response to hypoxia / G alpha (q) signalling events / cell population proliferation / G protein-coupled receptor signaling pathway / GTPase activity / dendrite / protein-containing complex binding / extracellular region / membrane / plasma membrane / cytoplasm
Similarity search - Function
Orexigenic neuropeptide QRFP/P518 / Orexigenic neuropeptide Qrfp/P518 / Neuropeptide Y receptor family / 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 ...Orexigenic neuropeptide QRFP/P518 / Orexigenic neuropeptide Qrfp/P518 / Neuropeptide Y receptor family / 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
Similarity search - Domain/homology
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 / Orexigenic neuropeptide QRFP / Pyroglutamylated RF-amide peptide receptor
Similarity search - Component
Biological speciesHomo sapiens (human) / Rattus norvegicus (Norway rat) / Bos taurus (cattle)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.73 Å
AuthorsJin S / Li X / Xu Y / Guo S / Wu C / Zhang H / Yuan Q / Xu HE / Xie X / Jiang Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81902085 China
CitationJournal: Cell Discov / Year: 2024
Title: Structural basis for recognition of 26RFa by the pyroglutamylated RFamide peptide receptor.
Authors: Sanshan Jin / Shimeng Guo / Youwei Xu / Xin Li / Canrong Wu / Xinheng He / Benxun Pan / Wenwen Xin / Heng Zhang / Wen Hu / Yuling Yin / Tianwei Zhang / Kai Wu / Qingning Yuan / H Eric Xu / Xin Xie / Yi Jiang /
Abstract: The neuropeptide 26RFa, a member of the RF-amide peptide family, activates the pyroglutamylated RF-amide peptide receptor (QRFPR), a class A GPCR. The 26RFa/QRFPR system plays critical roles in ...The neuropeptide 26RFa, a member of the RF-amide peptide family, activates the pyroglutamylated RF-amide peptide receptor (QRFPR), a class A GPCR. The 26RFa/QRFPR system plays critical roles in energy homeostasis, making QRFPR an attractive drug target for treating obesity, diabetes, and eating disorders. However, the lack of structural information has hindered our understanding of the peptide recognition and regulatory mechanism of QRFPR, impeding drug design efforts. In this study, we determined the cryo-EM structure of the G-coupled QRFPR bound to 26RFa. The structure reveals a unique assembly mode of the extracellular region of the receptor and the N-terminus of the peptide, and elucidates the recognition mechanism of the C-terminal heptapeptide of 26RFa by the transmembrane binding pocket of QRFPR. The study also clarifies the similarities and distinctions in the binding pattern of the RF-amide moiety in five RF-amide peptides and the RY-amide segment in neuropeptide Y. These findings deepen our understanding of the RF-amide peptide recognition, aiding in the rational design of drugs targeting QRFPR and other RF-amide peptide receptors.
History
DepositionNov 1, 2023-
Header (metadata) releaseJun 19, 2024-
Map releaseJun 19, 2024-
UpdateJun 19, 2024-
Current statusJun 19, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

Downloads & links

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Map

FileDownload / File: emd_37944.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 320 pix.
= 233.6 Å
0.73 Å/pix.
x 320 pix.
= 233.6 Å
0.73 Å/pix.
x 320 pix.
= 233.6 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.73 Å
Density
Contour LevelBy AUTHOR: 0.16
Minimum - Maximum-0.43322304 - 0.91497034
Average (Standard dev.)-0.0006595438 (±0.028024625)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 233.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #2

Fileemd_37944_additional_1.map
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Additional map: #1

Fileemd_37944_additional_2.map
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Half map: #2

Fileemd_37944_half_map_1.map
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Half map: #1

Fileemd_37944_half_map_2.map
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Sample components

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Entire : Structure of 26RFa-pyroglutamylated RFamide peptide receptor-G pr...

EntireName: Structure of 26RFa-pyroglutamylated RFamide peptide receptor-G protein complex
Components
  • Complex: Structure of 26RFa-pyroglutamylated RFamide peptide receptor-G protein complex
    • Protein or peptide: G-alpha q
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: scFV16
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Orexigenic neuropeptide QRFP
    • Protein or peptide: Pyroglutamylated RF-amide peptide receptor

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Supramolecule #1: Structure of 26RFa-pyroglutamylated RFamide peptide receptor-G pr...

SupramoleculeName: Structure of 26RFa-pyroglutamylated RFamide peptide receptor-G protein complex
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 160 KDa

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Macromolecule #1: G-alpha q

MacromoleculeName: G-alpha q / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.724383 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGCTLSAEDK AAVERSKMIE KQLQKDKQVY RRTLRLLLLG ADNSGKSTIV KQMRIYHVNG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMIE KQLQKDKQVY RRTLRLLLLG 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 IRKEFVDIST ASG DGRHIC YPHFTCSVDT ENARRIFNDC KDIILQMNLR EYNLV

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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: 37.41693 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
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: scFV16

MacromoleculeName: scFV16 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.277299 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSADIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
VQLVESGGGL VQPGGSRKLS CSASGFAFSS FGMHWVRQAP EKGLEWVAYI SSGSGTIYYA DTVKGRFTIS RDDPKNTLFL QMTSLRSED TAMYYCVRSI YYYGSSPFDF WGQGTTLTVS AGGGGSGGGG SGGGGSADIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL

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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: Bos taurus (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 #5: Orexigenic neuropeptide QRFP

MacromoleculeName: Orexigenic neuropeptide QRFP / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 2.882194 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
ASGPLGTLAE ELSSYSRRKG GFSFRFG

UniProtKB: Orexigenic neuropeptide QRFP

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Macromolecule #6: Pyroglutamylated RF-amide peptide receptor

MacromoleculeName: Pyroglutamylated RF-amide peptide receptor / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 49.54973 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MQALNITPEQ FSRLLRDHNL TREQFIALYR LRPLVYTPEL PGRAKLALVL TGVLIFALAL FGNALVFYVV TRSKAMRTVT NIFICSLAL SDLLITFFCI PVTMLQNISD NWLGGAFICK MVPFVQSTAV VTEILTMTCI AVERHQGLVH PFKMKWQYTN R RAFTMLGV ...String:
MQALNITPEQ FSRLLRDHNL TREQFIALYR LRPLVYTPEL PGRAKLALVL TGVLIFALAL FGNALVFYVV TRSKAMRTVT NIFICSLAL SDLLITFFCI PVTMLQNISD NWLGGAFICK MVPFVQSTAV VTEILTMTCI AVERHQGLVH PFKMKWQYTN R RAFTMLGV VWLVAVIVGS PMWHVQQLEI KYDFLYEKEH ICCLEEWTSP VHQKIYTTFI LVILFLLPLM VMLILYSKIG YE LWIKKRV GDGSVLRTIH GKEMSKIARK KKRAVIMMVT VVALFAVCWA PFHVVHMMIE YSNFEKEYDD VTIKMIFAIV QII GFSNSI CNPIVYAFMN ENFKKNVLSA VCYCIVNKTF SPAQRHGNSG ITMMRKKAKF SLRENPVEET KGEAFSDGNI EVKL CEQTE EKKKLKRHLA LFRSELAENS PLDSGH

UniProtKB: Pyroglutamylated RF-amide peptide receptor

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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: 7.2
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN 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: 5.0 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.73 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 202884
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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