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- PDB-8zh8: Human GPR103 -Gq complex bound to QRFP26 -

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Basic information

Entry
Database: PDB / ID: 8zh8
TitleHuman GPR103 -Gq complex bound to QRFP26
Components
  • (Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma- ...) x 2
  • Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
  • Pyroglutamylated RF-amide peptide receptor
  • QRF-amide
  • nanobody Nb35
  • scFv16
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / GPCR / MEMBRANE PROTEIN / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


orexigenic neuropeptide QRFP receptor binding / neuropeptide Y receptor activity / adenylate cyclase-activating serotonin receptor signaling pathway / Orexin and neuropeptides FF and QRFP bind to their respective receptors / regulation of feeding behavior / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / sensory perception of chemical stimulus / grooming behavior / negative regulation of calcium ion-dependent exocytosis / positive regulation of blood pressure ...orexigenic neuropeptide QRFP receptor binding / neuropeptide Y receptor activity / adenylate cyclase-activating serotonin receptor signaling pathway / Orexin and neuropeptides FF and QRFP bind to their respective receptors / regulation of feeding behavior / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / sensory perception of chemical stimulus / grooming behavior / negative regulation of calcium ion-dependent exocytosis / positive regulation of blood pressure / G protein-coupled adenosine receptor signaling pathway / mu-type opioid receptor binding / negative regulation of adenylate cyclase activity / neuropeptide hormone activity / corticotropin-releasing hormone receptor 1 binding / positive regulation of urine volume / positive regulation of neural precursor cell proliferation / 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 / negative regulation of synaptic transmission / Vasopressin regulates renal water homeostasis via Aquaporins / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / beta-2 adrenergic receptor binding / 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 / 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 / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (z) signalling events / Extra-nuclear estrogen signaling / photoreceptor outer segment membrane / G alpha (s) signalling events / G alpha (q) signalling events / spectrin binding / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / gamma-aminobutyric acid signaling pathway / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / alkylglycerophosphoethanolamine phosphodiesterase activity / regulation of calcium ion transport / negative regulation of apoptotic signaling pathway / PKA activation in glucagon signalling / developmental growth / photoreceptor outer segment / neuropeptide signaling pathway / D1 dopamine receptor binding / neuronal dense core vesicle / cellular response to hormone stimulus / Hedgehog 'off' state / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of superoxide anion generation / Adenylate cyclase inhibitory pathway / response to prostaglandin E / insulin-like growth factor receptor binding / adenylate cyclase regulator activity / cardiac muscle cell apoptotic process / photoreceptor inner segment / ionotropic glutamate receptor binding / response to nutrient / hippocampal mossy fiber to CA3 synapse / adenylate cyclase activator activity / Regulation of insulin secretion / locomotory behavior / G protein-coupled receptor binding / G protein-coupled receptor activity / bone development / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / platelet aggregation / G-protein beta/gamma-subunit complex binding / adenylate cyclase-activating G protein-coupled receptor signaling pathway
Similarity search - Function
Orexigenic neuropeptide QRFP/P518 / Orexigenic neuropeptide Qrfp/P518 / Neuropeptide Y receptor family / 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 ...Orexigenic neuropeptide QRFP/P518 / Orexigenic neuropeptide Qrfp/P518 / Neuropeptide Y receptor family / 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 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. / 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
Guanine nucleotide-binding protein G(i) subunit alpha-2 / 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 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Orexigenic neuropeptide QRFP / Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas / Pyroglutamylated RF-amide peptide receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
Rattus norvegicus (Norway rat)
Bos taurus (domestic cattle)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.19 Å
AuthorsIwama, A. / Akasaka, H. / Sano, F.K. / Oshima, H.S. / Shihoya, W. / Nureki, O.
Funding support Japan, 1items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)21H05037 Japan
CitationJournal: Nat Commun / Year: 2024
Title: Structure and dynamics of the pyroglutamylated RF-amide peptide QRFP receptor GPR103.
Authors: Aika Iwama / Ryoji Kise / Hiroaki Akasaka / Fumiya K Sano / Hidetaka S Oshima / Asuka Inoue / Wataru Shihoya / Osamu Nureki /
Abstract: Pyroglutamylated RF-amide peptide (QRFP) is a peptide hormone with a C-terminal RF-amide motif. QRFP selectively activates a class A G-protein-coupled receptor (GPCR) GPR103 to exert various ...Pyroglutamylated RF-amide peptide (QRFP) is a peptide hormone with a C-terminal RF-amide motif. QRFP selectively activates a class A G-protein-coupled receptor (GPCR) GPR103 to exert various physiological functions such as energy metabolism and appetite regulation. Here, we report the cryo-electron microscopy structure of the QRFP26-GPR103-G complex at 3.19 Å resolution. QRFP26 adopts an extended structure bearing no secondary structure, with its N-terminal and C-terminal sides recognized by extracellular and transmembrane domains of GPR103 respectively. This movement, reminiscent of class B1 GPCRs except for orientation and structure of the ligand, is critical for the high-affinity binding and receptor specificity of QRFP26. Mutagenesis experiments validate the functional importance of the binding mode of QRFP26 by GPR103. Structural comparisons with closely related receptors, including RY-amide peptide-recognizing GPCRs, revealed conserved and diversified peptide recognition mechanisms, providing profound insights into the biological significance of RF-amide peptides. Collectively, this study not only advances our understanding of GPCR-ligand interactions, but also paves the way for the development of novel therapeutics targeting metabolic and appetite disorders and emergency medical care.
History
DepositionMay 10, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 3, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
R: Pyroglutamylated RF-amide peptide receptor
N: nanobody Nb35
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
A: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2,Guanine nucleotide-binding protein G(i) subunit alpha-2,Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas
S: scFv16
Q: QRF-amide


Theoretical massNumber of molelcules
Total (without water)174,0897
Polymers174,0897
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 2 molecules RB

#1: Protein Pyroglutamylated RF-amide peptide receptor / AQ27 / G-protein coupled receptor 103 / Orexigenic neuropeptide QRFP receptor / SP9155


Mass: 45652.039 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: QRFPR, GPR103 / Cell line (production host): HEK293S GnTI- / Production host: Homo sapiens (human) / References: UniProt: Q96P65
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38744.371 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gnb1 / Cell line (production host): HEK293S GnTI- / Production host: Homo sapiens (human) / References: UniProt: P54311

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Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma- ... , 2 types, 2 molecules GA

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


Mass: 7547.685 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: GNG2 / Cell line (production host): HEK293S GnTI- / Production host: Homo sapiens (human) / References: UniProt: P63212
#5: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2,Guanine nucleotide-binding protein G(i) subunit alpha-2,Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas / G gamma-I / Adenylate cyclase-inhibiting G alpha protein / Adenylate cyclase-stimulating G alpha ...G gamma-I / Adenylate cyclase-inhibiting G alpha protein / Adenylate cyclase-stimulating G alpha protein / Extra large alphas protein / XLalphas


Mass: 36573.531 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2, GNAI2, GNAI2B, GNAS, GNAS1 / Cell line (production host): HEK293S GnTI- / Production host: Homo sapiens (human)
References: UniProt: P59768, UniProt: P04899, UniProt: Q5JWF2

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Protein/peptide , 1 types, 1 molecules Q

#7: Protein/peptide QRF-amide / Neuropeptide RF-amide / Pyroglutamylated arginine-phenylalanine-amide peptide


Mass: 2835.161 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P83859

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Antibody , 2 types, 2 molecules NS

#2: Antibody nanobody Nb35


Mass: 15015.728 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)
#6: Antibody scFv16


Mass: 27720.795 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)

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Details

Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human GPR103 -Gq complex bound to QRFP26 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1600 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 0.83 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.19 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 142831 / Symmetry type: POINT

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