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- PDB-8k6n: Structural complex of neuropeptide Y receptor 2 -

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Basic information

Entry
Database: PDB / ID: 8k6n
TitleStructural complex of neuropeptide Y receptor 2
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • C-flanking peptide of NPY
  • Neuropeptide Y receptor type 2
  • scFV16
KeywordsMEMBRANE PROTEIN / neuropeptide Y receptor 2 / complex
Function / homology
Function and homology information


negative regulation of nervous system process / regulation of nerve growth factor production / peptide YY receptor activity / short-day photoperiodism / negative regulation of acute inflammatory response to antigenic stimulus / positive regulation of circadian sleep/wake cycle, non-REM sleep / positive regulation of peptide secretion / neuropeptide Y receptor activity / monocyte activation / positive regulation of dopamine metabolic process ...negative regulation of nervous system process / regulation of nerve growth factor production / peptide YY receptor activity / short-day photoperiodism / negative regulation of acute inflammatory response to antigenic stimulus / positive regulation of circadian sleep/wake cycle, non-REM sleep / positive regulation of peptide secretion / neuropeptide Y receptor activity / monocyte activation / positive regulation of dopamine metabolic process / : / positive regulation of appetite / neuropeptide Y receptor binding / intestinal epithelial cell differentiation / positive regulation of eating behavior / negative regulation of secretion / synaptic signaling via neuropeptide / cardiac left ventricle morphogenesis / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / adult feeding behavior / positive regulation of smooth muscle contraction / regulation of presynaptic cytosolic calcium ion concentration / negative regulation of calcium ion-dependent exocytosis / negative regulation of excitatory postsynaptic potential / positive regulation of dopamine secretion / G protein-coupled adenosine receptor signaling pathway / negative regulation of adenylate cyclase activity / neuropeptide hormone activity / positive regulation of urine volume / positive regulation of neural precursor cell proliferation / feeding behavior / negative regulation of synaptic transmission / negative regulation of cAMP/PKA signal transduction / non-motile cilium / negative regulation of synaptic transmission, glutamatergic / positive regulation of cell-substrate adhesion / negative regulation of feeding behavior / gamma-aminobutyric acid signaling pathway / regulation of synaptic vesicle exocytosis / central nervous system neuron development / outflow tract morphogenesis / regulation of calcium ion transport / negative regulation of apoptotic signaling pathway / nitric oxide mediated signal transduction / 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 / neuronal dense core vesicle / behavioral fear response / Adenylate cyclase inhibitory pathway / positive regulation of vascular associated smooth muscle cell proliferation / negative regulation of blood pressure / positive regulation of superoxide anion generation / response to nutrient / Peptide ligand-binding receptors / hippocampal mossy fiber to CA3 synapse / calcium channel regulator activity / Regulation of insulin secretion / locomotory behavior / G protein-coupled receptor binding / G protein-coupled receptor activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / cerebral cortex development / GABA-ergic synapse / G-protein beta/gamma-subunit complex binding / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / terminal bouton / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / neuron projection development / 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 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / 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 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding
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 / Serpentine type 7TM GPCR chemoreceptor Srsx ...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 / Serpentine type 7TM GPCR chemoreceptor Srsx / 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
Pro-neuropeptide Y / Guanine nucleotide-binding protein G(i) subunit alpha-2 / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsShen, S.Y. / Zhao, C. / Shao, Z.H.
Funding support China, 1items
OrganizationGrant numberCountry
Other government China
CitationJournal: MedComm (2020) / Year: 2024
Title: Structural basis of neuropeptide Y signaling through Y and Y receptors.
Authors: Siyuan Shen / Yue Deng / Chenglong Shen / Haidi Chen / Lin Cheng / Chao Wu / Chang Zhao / Zhiqian Yang / Hanlin Hou / Kexin Wang / Zhenhua Shao / Cheng Deng / Feng Ye / Wei Yan /
Abstract: Neuropeptide Y (NPY), a 36-amino-acid peptide, functions as a neurotransmitter in both the central and peripheral nervous systems by activating the NPY receptor subfamily. Notably, NPY analogs ...Neuropeptide Y (NPY), a 36-amino-acid peptide, functions as a neurotransmitter in both the central and peripheral nervous systems by activating the NPY receptor subfamily. Notably, NPY analogs display varying selectivity and exert diverse physiological effects through their interactions with this receptor family. [Pro]-NPY and [Leu, Pro]-NPY, mainly acting on YR, reportedly increases blood pressure and postsynaptically potentiates the effect of other vasoactive substances above all, while N-terminal cleaved NPY variants in human body primary mediates angiogenesis and neurotransmitter release inhibition through YR. However, the recognition mechanisms of YR and YR with specific agonists remain elusive, thereby hindering subtype receptor-selective drug development. In this study, we report three cryo-electron microscopy (cryo-EM) structures of Gi2-coupled YR and YR in complexes with NPY, as well as YR bound to a selective agonist [Leu, Pro]-NPY. Combined with cell-based assays, our study not only reveals the conserved peptide-binding mode of NPY receptors but also identifies an additional sub-pocket that confers ligand selectivity. Moreover, our analysis of YR evolutionary dynamics suggests that this sub-pocket has undergone functional adaptive evolution across different species. Collectively, our findings shed light on the molecular underpinnings of neuropeptide recognition and receptor activation, and they present a promising avenue for the design of selective drugs targeting the NPY receptor family.
History
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-2
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
D: C-flanking peptide of NPY
E: Neuropeptide Y receptor type 2
S: scFV16


Theoretical massNumber of molelcules
Total (without water)158,7426
Polymers158,7426
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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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABC

#1: Protein Guanine nucleotide-binding protein G(i) subunit alpha-2 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40502.863 Da / Num. of mol.: 1 / Mutation: S47N,G204A,E246A,A327S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI2, GNAI2B / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P04899
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 39141.793 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / 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: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Protein/peptide / Protein / Antibody , 3 types, 3 molecules DES

#4: Protein/peptide C-flanking peptide of NPY / Neuropeptide Y / CPON


Mass: 4278.720 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01303
#5: Protein Neuropeptide Y receptor type 2 / NPY2-R / NPY-Y2 receptor / Y2 receptor


Mass: 38321.039 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NPY2R / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P49146
#6: Antibody scFV16


Mass: 28636.793 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 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: Structural complex of neuropeptide Y receptor 1 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
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: 1800 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 57 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 738846 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0039485
ELECTRON MICROSCOPYf_angle_d0.59512849
ELECTRON MICROSCOPYf_dihedral_angle_d4.9141282
ELECTRON MICROSCOPYf_chiral_restr0.0441466
ELECTRON MICROSCOPYf_plane_restr0.0041619

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