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- PDB-7vgx: Neuropeptide Y Y1 Receptor (NPY1R) in Complex with G Protein and ... -

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Entry
Database: PDB / ID: 7vgx
TitleNeuropeptide Y Y1 Receptor (NPY1R) in Complex with G Protein and its endogeneous Peptide-Agonist Neuropeptide Y (NPY)
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • (Neuropeptide ...) x 2
  • single-chain antibody Fv fragment (scFv16)
KeywordsMEMBRANE PROTEIN / NPY / GPCR / G-protein / Complex
Function / homology
Function and homology information


pancreatic polypeptide receptor activity / peptide YY receptor activity / neuropeptide Y receptor activity / positive regulation of appetite / neuropeptide Y receptor binding / intestinal epithelial cell differentiation / synaptic signaling via neuropeptide / adult feeding behavior / neuropeptide receptor activity / neuropeptide hormone activity ...pancreatic polypeptide receptor activity / peptide YY receptor activity / neuropeptide Y receptor activity / positive regulation of appetite / neuropeptide Y receptor binding / intestinal epithelial cell differentiation / synaptic signaling via neuropeptide / adult feeding behavior / neuropeptide receptor activity / neuropeptide hormone activity / neuropeptide binding / feeding behavior / neuronal dense core vesicle / central nervous system neuron development / outflow tract morphogenesis / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / regulation of multicellular organism growth / neuropeptide signaling pathway / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / positive regulation of protein localization to cell cortex / Adenylate cyclase inhibitory pathway / T cell migration / D2 dopamine receptor binding / response to prostaglandin E / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / calcium channel regulator activity / sensory perception of pain / cellular response to forskolin / regulation of mitotic spindle organization / Peptide ligand-binding receptors / GABA-ergic synapse / locomotory behavior / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G protein-coupled receptor activity / cerebral cortex development / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / regulation of blood pressure / response to peptide hormone / G-protein beta/gamma-subunit complex binding / centriolar satellite / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / glucose metabolic process / 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 / Sensory perception of sweet, bitter, and umami (glutamate) taste / neuron projection development / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / GDP binding / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / 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) / G protein activity / GTPase binding / Ca2+ pathway / retina development in camera-type eye / midbody / cell cortex / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / chemical synaptic transmission / G alpha (q) signalling events
Similarity search - Function
Neuropeptide Y1 receptor / Neuropeptide Y receptor family / Pancreatic hormone-like / Pancreatic hormone-like, conserved site / Pancreatic hormone peptide / Pancreatic hormone family signature. / Pancreatic hormone family profile. / Pancreatic hormones / neuropeptide F / peptide YY family / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase ...Neuropeptide Y1 receptor / Neuropeptide Y receptor family / Pancreatic hormone-like / Pancreatic hormone-like, conserved site / Pancreatic hormone peptide / Pancreatic hormone family signature. / Pancreatic hormone family profile. / Pancreatic hormones / neuropeptide F / peptide YY family / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / 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 / 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 / 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 / Immunoglobulins / Immunoglobulin-like / Sandwich / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
Pro-neuropeptide Y / Neuropeptide Y 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 / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsPark, C. / Kim, J. / Jeong, H. / Kang, H. / Bang, I. / Choi, H.-J.
Funding support Korea, Republic Of, 2items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea)NRF-2019M3E5D6063903 Korea, Republic Of
National Research Foundation (NRF, Korea)2020R1A2C2003783 Korea, Republic Of
CitationJournal: Nat Commun / Year: 2022
Title: Structural basis of neuropeptide Y signaling through Y1 receptor.
Authors: Chaehee Park / Jinuk Kim / Seung-Bum Ko / Yeol Kyo Choi / Hyeongseop Jeong / Hyeonuk Woo / Hyunook Kang / Injin Bang / Sang Ah Kim / Tae-Young Yoon / Chaok Seok / Wonpil Im / Hee-Jung Choi /
Abstract: Neuropeptide Y (NPY) is highly abundant in the brain and involved in various physiological processes related to food intake and anxiety, as well as human diseases such as obesity and cancer. However, ...Neuropeptide Y (NPY) is highly abundant in the brain and involved in various physiological processes related to food intake and anxiety, as well as human diseases such as obesity and cancer. However, the molecular details of the interactions between NPY and its receptors are poorly understood. Here, we report a cryo-electron microscopy structure of the NPY-bound neuropeptide Y1 receptor (YR) in complex with G protein. The NPY C-terminal segment forming the extended conformation binds deep into the YR transmembrane core, where the amidated C-terminal residue Y36 of NPY is located at the base of the ligand-binding pocket. Furthermore, the helical region and two N-terminal residues of NPY interact with YR extracellular loops, contributing to the high affinity of NPY for YR. The structural analysis of NPY-bound YR and mutagenesis studies provide molecular insights into the activation mechanism of YR upon NPY binding.
History
DepositionSep 19, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 23, 2022Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
R: Neuropeptide Y receptor type 1
L: Neuropeptide Y
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
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
S: single-chain antibody Fv fragment (scFv16)


Theoretical massNumber of molelcules
Total (without water)164,5546
Polymers164,5546
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, Complex eluted at proper elution volume
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Neuropeptide ... , 2 types, 2 molecules RL

#1: Protein Neuropeptide Y receptor type 1 / NPY1-R


Mass: 46489.961 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NPY1R, NPYR, NPYY1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P25929
#2: Protein/peptide Neuropeptide Y / Neuropeptide tyrosine / NPY


Mass: 4277.735 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01303

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#3: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40427.969 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Escherichia coli (E. coli) / References: UniProt: P63096
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37728.152 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#5: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7845.078 Da / Num. of mol.: 1 / Mutation: C68S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Antibody , 1 types, 1 molecules S

#6: Antibody single-chain antibody Fv fragment (scFv16)


Mass: 27784.896 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Cell line (production host): Hi5 / Production host: Trichoplusia ni (cabbage looper)

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Details

Has ligand of interestY
Sequence detailsLast 11 residues (AAAHHHHHHHH) of chain S are expression tags.

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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

Component
IDNameTypeEntity IDParent-IDSource
1Complex of Neuropeptide Y Y1 Receptor (NPY1R) with its endogeneous Peptide-Agonist Neuropeptide Y (NPY), G Protein and G-protein stabilizing antibody fragement (scFv16)COMPLEXall0MULTIPLE SOURCES
2Neuropeptide Y Y1 Receptor (NPY1R)COMPLEX#11RECOMBINANT
3nucleotide-free G-Protein heterotrimerCOMPLEX#3-#51RECOMBINANT
4Neuropeptide YCOMPLEX#21SYNTHETIC
5single-chain antibody Fv fragment (scFv16)COMPLEX#61RECOMBINANT
Molecular weightValue: 0.16 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
55Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Spodoptera frugiperda (fall armyworm)7108
33Spodoptera frugiperda (fall armyworm)7108
43Escherichia coli (E. coli)562
55Trichoplusia ni (cabbage looper)7111
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMhydroxyethyl piperazine ethane sulfonicacidHEPES1
2150 mMsodium chlorideNaCl1
30.01 %glyco-diosgeninGDN1
SpecimenConc.: 10 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 285 K / Details: blot for 5 seconds before plunging

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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 magnification: 75000 X / Nominal defocus max: 3750 nm / Nominal defocus min: 1250 nm / Cs: 0.1 mm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 40 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k)
EM imaging opticsSpherical aberration corrector: Microscope was modified with a Cs corrector
Image scansWidth: 4096 / Height: 4096

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.19.2_4158refinement
PHENIX1.19.2_4158refinement
EM software
IDNameVersionCategory
1Topaz0.2.4particle selection
4cryoSPARC3.2.0CTF correction
7PHENIX1.19.2-4158model fitting
9PHENIX1.19.2-4158model refinement
10cryoSPARC3.2.0initial Euler assignment
11cryoSPARC3.2.0final Euler assignment
13cryoSPARC3.2.03D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1339224
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 233117 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model building
IDPDB-IDPdb chain-ID 3D fitting-ID
15ZBH

5zbh

A1
26OS9

6os9

A1
36OS9

6os9

B1
46OS9

6os9

C1
56OS9

6os9

D1
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 71.54 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00379234
ELECTRON MICROSCOPYf_angle_d0.632712506
ELECTRON MICROSCOPYf_chiral_restr0.04541415
ELECTRON MICROSCOPYf_plane_restr0.00341583
ELECTRON MICROSCOPYf_dihedral_angle_d12.79133318

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