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- PDB-7x9b: Cryo-EM structure of neuropeptide Y Y2 receptor in complex with N... -

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Basic information

Entry
Database: PDB / ID: 7x9b
TitleCryo-EM structure of neuropeptide Y Y2 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 2
KeywordsSIGNALING PROTEIN
Function / homology
Function and homology information


peptide YY receptor activity / neuropeptide Y receptor activity / positive regulation of appetite / neuropeptide Y receptor binding / intestinal epithelial cell differentiation / synaptic signaling via neuropeptide / cardiac left ventricle morphogenesis / adult feeding behavior / neuropeptide hormone activity / feeding behavior ...peptide YY receptor activity / neuropeptide Y receptor activity / positive regulation of appetite / neuropeptide Y receptor binding / intestinal epithelial cell differentiation / synaptic signaling via neuropeptide / cardiac left ventricle morphogenesis / adult feeding behavior / neuropeptide hormone activity / feeding behavior / non-motile cilium / neuronal dense core vesicle / central nervous system neuron development / outflow tract morphogenesis / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / 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 / 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 / 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 / signaling receptor 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 / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation
Similarity search - Function
Neuropeptide Y2 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 Y2 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 / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 / P-loop containing nucleoside triphosphate hydrolase / Mainly Beta
Similarity search - Domain/homology
Pro-neuropeptide Y / Neuropeptide Y receptor type 2 / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 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:
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Assembly

Deposited unit
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
R: Neuropeptide Y receptor type 2
P: Neuropeptide Y


Theoretical massNumber of molelcules
Total (without water)135,0355
Polymers135,0355
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 Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40414.047 Da / Num. of mol.: 1
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
#2: 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 / Mutation: S47N, G203A, E245A, A326S
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
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P59768
#4: Protein Neuropeptide Y receptor type 2 / NPY2-R / NPY-Y2 receptor / Y2 receptor


Mass: 43737.883 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NPY2R / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P49146
#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 Y2 receptor in complex with NPY and GiCOMPLEXall0MULTIPLE SOURCES
2Neuropeptide Y Y2 receptor and GiCOMPLEX#1-#41RECOMBINANT
3Neuropeptide YCOMPLEX#51SYNTHETIC
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper) / Plasmid: Homo sapiens
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: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 361477 / Symmetry type: POINT
RefinementStereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 124.46 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00167391
ELECTRON MICROSCOPYf_angle_d0.493910050
ELECTRON MICROSCOPYf_chiral_restr0.03951183
ELECTRON MICROSCOPYf_plane_restr0.00331262
ELECTRON MICROSCOPYf_dihedral_angle_d18.52262573

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