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- PDB-7x9a: Cryo-EM structure of neuropeptide Y Y1 receptor in complex with N... -

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Basic information

Entry
Database: PDB / ID: 7x9a
TitleCryo-EM structure of neuropeptide Y Y1 receptor in complex with NPY and Gi
Components
  • 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
  • Neuropeptide Y
  • Neuropeptide Y receptor type 1
KeywordsSIGNALING PROTEIN
Function / homology
Function and homology information


pancreatic polypeptide receptor activity / regulation of nerve growth factor production / : / peptide YY receptor activity / short-day photoperiodism / negative regulation of acute inflammatory response to antigenic stimulus / neuropeptide Y receptor activity / monocyte activation / positive regulation of dopamine metabolic process / neuropeptide Y receptor binding ...pancreatic polypeptide receptor activity / regulation of nerve growth factor production / : / peptide YY receptor activity / short-day photoperiodism / negative regulation of acute inflammatory response to antigenic stimulus / neuropeptide Y receptor activity / monocyte activation / positive regulation of dopamine metabolic process / neuropeptide Y receptor binding / intestinal epithelial cell differentiation / positive regulation of appetite / synaptic signaling via neuropeptide / positive regulation of eating behavior / adult feeding behavior / neuropeptide receptor activity / regulation of presynaptic cytosolic calcium ion concentration / drinking behavior / neuropeptide hormone activity / positive regulation of cell-substrate adhesion / feeding behavior / neuropeptide binding / regulation of synaptic vesicle exocytosis / central nervous system neuron development / regulation of multicellular organism growth / outflow tract morphogenesis / developmental growth / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / neuronal dense core vesicle / negative regulation of blood pressure / regulation of eating behavior / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / T cell migration / positive regulation of relaxation of smooth muscle / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / sensory perception of pain / adenylate cyclase-inhibiting serotonin receptor signaling pathway / G protein-coupled serotonin receptor binding / cellular response to forskolin / mast cell degranulation / Peptide ligand-binding receptors / regulation of mitotic spindle organization / chemokine-mediated signaling pathway / calcium channel regulator activity / locomotory behavior / Regulation of insulin secretion / neuropeptide signaling pathway / response to prostaglandin E / cerebral cortex development / positive regulation of cholesterol biosynthetic process / glucose metabolic process / G protein-coupled receptor binding / regulation of blood pressure / response to peptide hormone / GABA-ergic synapse / G protein-coupled receptor activity / neuron projection development / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / terminal bouton / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / G beta:gamma signalling through BTK / photoreceptor disc membrane / GDP binding / ADP signalling through P2Y purinoceptor 12 / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / G alpha (12/13) signalling events / extracellular vesicle / sensory perception of taste
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 / Rhopdopsin 7-helix transmembrane proteins / Rhodopsin 7-helix transmembrane proteins ...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 / Rhopdopsin 7-helix transmembrane proteins / Rhodopsin 7-helix transmembrane proteins / YVTN repeat-like/Quinoprotein amine dehydrogenase / G-protein alpha subunit, group I / 7 Propeller / Methylamine Dehydrogenase; Chain H / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 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 / Up-down Bundle / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
Pro-neuropeptide Y / Neuropeptide Y receptor type 1 / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsTang, T. / Han, S. / Zhao, Q. / Wu, B.
Funding support China, 3items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)31825010 China
National Science Foundation (NSF, China)82121005 China
National Science Foundation (NSF, China)32161133011 China
CitationJournal: Sci Adv / Year: 2022
Title: Receptor-specific recognition of NPY peptides revealed by structures of NPY receptors.
Authors: Tingting Tang / Qiuxiang Tan / Shuo Han / Anne Diemar / Kristin Löbner / Hongyu Wang / Corinna Schüß / Victoria Behr / Karin Mörl / Mu Wang / Xiaojing Chu / Cuiying Yi / Max Keller / ...Authors: Tingting Tang / Qiuxiang Tan / Shuo Han / Anne Diemar / Kristin Löbner / Hongyu Wang / Corinna Schüß / Victoria Behr / Karin Mörl / Mu Wang / Xiaojing Chu / Cuiying Yi / Max Keller / Jacob Kofoed / Steffen Reedtz-Runge / Anette Kaiser / Annette G Beck-Sickinger / Qiang Zhao / Beili Wu /
Abstract: In response to three highly conserved neuropeptides, neuropeptide Y (NPY), peptide YY, and pancreatic polypeptide (PP), four G protein-coupled receptors mediate multiple essential physiological ...In response to three highly conserved neuropeptides, neuropeptide Y (NPY), peptide YY, and pancreatic polypeptide (PP), four G protein-coupled receptors mediate multiple essential physiological processes, such as food intake, vasoconstriction, sedation, and memory retention. Here, we report the structures of the human Y, Y, and Y receptors in complex with NPY or PP, and the G protein. These structures reveal distinct binding poses of the peptide upon coupling to different receptors, reflecting the importance of the conformational plasticity of the peptide in recognizing the NPY receptors. The N terminus of the peptide forms extensive interactions with the Y receptor, but not with the Y and Y receptors. Supported by mutagenesis and functional studies, subtype-specific interactions between the receptors and peptides were further observed. These findings provide insight into key factors that govern NPY signal recognition and transduction, and would enable development of selective drugs.
History
DepositionMar 15, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 18, 2022Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
R: Neuropeptide Y receptor type 1
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
P: Neuropeptide Y


Theoretical massNumber of molelcules
Total (without water)134,7605
Polymers134,7605
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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


Mass: 43462.648 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NPY1R, NPYR, NPYY1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P25929
#2: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40414.047 Da / Num. of mol.: 1 / Mutation: S47N, G203A, E245A, A326S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P63096
#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.) Homo sapiens (human) / Gene: GNB1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P62873
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Trichoplusia ni (cabbage looper)
#5: 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
Has ligand of interestN

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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
1Neuropeptide Y Y1 receptor in complex with NPY and GiCOMPLEXall0MULTIPLE SOURCES
2Neuropeptide Y Y1 receptor and GiCOMPLEX#1-#41RECOMBINANT
3Neuropeptide YCOMPLEX#51SYNTHETIC
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.5
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: 2300 nm / Nominal defocus min: 1300 nm
Image recordingElectron dose: 70 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.18.2_3874refinement
PHENIX1.18.2_3874refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 423400 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 92.41 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00177310
ELECTRON MICROSCOPYf_angle_d0.4749966
ELECTRON MICROSCOPYf_chiral_restr0.03881178
ELECTRON MICROSCOPYf_plane_restr0.00271262
ELECTRON MICROSCOPYf_dihedral_angle_d15.62852471

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