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- PDB-8jbf: Senktide bound to active human neurokinin 3 receptor in complex w... -

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Entry
Database: PDB / ID: 8jbf
TitleSenktide bound to active human neurokinin 3 receptor in complex with Gq
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Neuromedin-K receptor
  • ScFv16 nanobody
  • Senktide
KeywordsMEMBRANE PROTEIN / G protein coupled receptor / Neurokinin / Cryo-EM / Peptide Agonists
Function / homology
Function and homology information


tachykinin receptor activity / positive regulation of flagellated sperm motility / Tachykinin receptors bind tachykinins / positive regulation of uterine smooth muscle contraction / tachykinin receptor signaling pathway / regulation of feeding behavior / regulation of dopamine metabolic process / positive regulation of blood pressure / G-protein activation / Activation of the phototransduction cascade ...tachykinin receptor activity / positive regulation of flagellated sperm motility / Tachykinin receptors bind tachykinins / positive regulation of uterine smooth muscle contraction / tachykinin receptor signaling pathway / regulation of feeding behavior / regulation of dopamine metabolic process / positive regulation of blood pressure / 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 / Vasopressin regulates renal water homeostasis via Aquaporins / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / G alpha (i) signalling events / 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 / Thrombin signalling through proteinase activated receptors (PARs) / 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 / G alpha (s) signalling events / photoreceptor outer segment membrane / neuronal cell body membrane / G alpha (q) signalling events / G alpha (i) signalling events / spectrin binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / 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 / photoreceptor outer segment / positive regulation of heart rate / photoreceptor inner segment / dendrite membrane / cardiac muscle cell apoptotic process / sperm midpiece / response to cocaine / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / sensory perception of taste / response to estradiol / signaling receptor complex adaptor activity / cell body / GTPase binding / positive regulation of cytosolic calcium ion concentration / retina development in camera-type eye / phospholipase C-activating G protein-coupled receptor signaling pathway / cellular response to hypoxia / G alpha (q) signalling events / cell population proliferation / G protein-coupled receptor signaling pathway / GTPase activity / synapse / dendrite / protein-containing complex binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
Neurokinin NK3 receptor / Neurokinin receptor / 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 ...Neurokinin NK3 receptor / Neurokinin receptor / 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
Similarity search - Domain/homology
Neuromedin-K receptor / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
Rattus norvegicus (Norway rat)
Mus musculoides (Temminck's mouse)
Bos taurus (domestic cattle)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsSun, W.J. / Yang, F. / Zhang, H.H. / Yuan, Q.N. / Yin, W.C. / Shi, P. / Eric, X. / Tian, C.L.
Funding support China, 1items
OrganizationGrant numberCountry
Other government China
CitationJournal: Cell Discov / Year: 2023
Title: Structural insights into neurokinin 3 receptor activation by endogenous and analogue peptide agonists.
Authors: Wenjing Sun / Fan Yang / Huanhuan Zhang / Qingning Yuan / Shenglong Ling / Yuanxia Wang / Pei Lv / Zelin Li / Yifan Luo / Dongsheng Liu / Wanchao Yin / Pan Shi / H Eric Xu / Changlin Tian /
Abstract: Neurokinin 3 receptor (NK3R) is a tachykinin receptor essential for the hypothalamic-pituitary-gonadal axis. The endogenous peptide agonist neurokinin B (NKB) preferentially activates NK3R, while ...Neurokinin 3 receptor (NK3R) is a tachykinin receptor essential for the hypothalamic-pituitary-gonadal axis. The endogenous peptide agonist neurokinin B (NKB) preferentially activates NK3R, while substance P (SP) binds preferentially to NK1R. In addition, the SP analogue senktide more potently activates NK3R than NKB and SP. However, the mechanisms of preferential binding of peptide and NK3R activation remain elusive. Herein, we determined the cryogenic electron microscopy (cryo-EM) structures of the NK3R-G complex bound to NKB, SP and senktide. The three NK3R-G/peptide complexes utilize a class of noncanonical receptor activation mechanisms. Combining the structural analysis and functional assay illustrated that the consensus C-termini of the three peptide agonists share a conserved binding mode to NK3R, while the divergent N-termini of the peptides confer the preferential binding of the agonist to NK3R. In addition, the specific interactions between the N-terminus of senktide and the N-terminus and extracellular loops (ECL2 and ECL3) of NK3R lead to the improved activation displayed by senktide compared to SP and NKB. These findings pave the way to understand tachykinin receptor subtype selectivity and provide ideas to rationally develop drugs targeting NK3R.
History
DepositionMay 8, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 28, 2024Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
B: Neuromedin-K receptor
D: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
E: ScFv16 nanobody
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
A: Senktide
C: Guanine nucleotide-binding protein Gq subunit alpha


Theoretical massNumber of molelcules
Total (without water)168,5396
Polymers168,5396
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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

#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 41042.828 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gnb1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P54311
#4: 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.) Bos taurus (domestic cattle) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63212
#6: Protein Guanine nucleotide-binding protein Gq subunit alpha


Mass: 41694.289 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)

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

#1: Protein Neuromedin-K receptor / NKR / NK-3 receptor / NK-3R / Neurokinin B receptor / Tachykinin receptor 3


Mass: 44317.020 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: NK3R-pFastbac1 / Source: (gene. exp.) Homo sapiens (human) / Gene: TACR3, NK3R, TAC3R / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P29371
#3: Antibody ScFv16 nanobody


Mass: 32708.473 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculoides (Temminck's mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#5: Protein/peptide Senktide


Mass: 915.022 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)

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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: Senktide bound to active human neurokinin 3 receptor in complex with Gq heterotrimer
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE / Humidity: 100 %

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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: SPOT SCAN
Electron lensMode: DIFFRACTION / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm
Image recordingElectron dose: 50 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 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 2457160 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0059009
ELECTRON MICROSCOPYf_angle_d0.57412234
ELECTRON MICROSCOPYf_dihedral_angle_d4.6861228
ELECTRON MICROSCOPYf_chiral_restr0.0441387
ELECTRON MICROSCOPYf_plane_restr0.0041548

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