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- EMDB-36144: Senktide bound to active human neurokinin 3 receptor in complex w... -

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Entry
Database: EMDB / ID: EMD-36144
TitleSenktide bound to active human neurokinin 3 receptor in complex with Gq
Map dataSenktide bound to active human neurokinin 3 receptor in complex with Gq
Sample
  • Complex: Senktide bound to active human neurokinin 3 receptor in complex with Gq heterotrimer
    • Protein or peptide: Neuromedin-K receptor
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: ScFv16 nanobody
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Senktide
    • Protein or peptide: Guanine nucleotide-binding protein Gq subunit alpha
KeywordsG protein coupled receptor / Neurokinin / Cryo-EM / Peptide Agonists / MEMBRANE PROTEIN
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 / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / 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 / Glucagon-type ligand receptors / G alpha (12/13) signalling events / 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 / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / G alpha (z) signalling events / G alpha (s) signalling events / Extra-nuclear estrogen signaling / G alpha (q) signalling events / photoreceptor outer segment membrane / neuronal cell body membrane / spectrin binding / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / alkylglycerophosphoethanolamine phosphodiesterase activity / photoreceptor outer segment / positive regulation of heart rate / dendrite membrane / cardiac muscle cell apoptotic process / sperm midpiece / photoreceptor inner segment / response to cocaine / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / sensory perception of taste / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / response to estradiol / GTPase binding / retina development in camera-type eye / positive regulation of cytosolic calcium ion concentration / cell body / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / cellular response to hypoxia / cell population proliferation / G protein-coupled receptor signaling pathway / GTPase activity / dendrite / synapse / 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. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / 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 (cattle)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsSun WJ / Yang F / Zhang HH / Yuan QN / Yin WC / Shi P / Eric X / Tian CL
Funding support China, 1 items
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, 2023-
Header (metadata) releaseFeb 28, 2024-
Map releaseFeb 28, 2024-
UpdateFeb 28, 2024-
Current statusFeb 28, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36144.png

Downloads & links

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Map

FileDownload / File: emd_36144.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSenktide bound to active human neurokinin 3 receptor in complex with Gq
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.03 Å/pix.
x 256 pix.
= 263.68 Å		1.03 Å/pix.
x 256 pix.
= 263.68 Å		1.03 Å/pix.
x 256 pix.
= 263.68 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.03 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.085
Minimum - Maximum-0.0016586429 - 1.6806942
Average (Standard dev.)0.0009786922 (±0.021833321)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 263.68 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Senktide bound to active human neurokinin 3 receptor...

Fileemd_36144_half_map_1.map
AnnotationSenktide bound to active human neurokinin 3 receptor in complex with Gq
Projections & Slices
AxesZYX

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Histogram (log scale)

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Half map: Senktide bound to active human neurokinin 3 receptor...

Fileemd_36144_half_map_2.map
AnnotationSenktide bound to active human neurokinin 3 receptor in complex with Gq
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Senktide bound to active human neurokinin 3 receptor in complex w...

EntireName: Senktide bound to active human neurokinin 3 receptor in complex with Gq heterotrimer
Components
  • Complex: Senktide bound to active human neurokinin 3 receptor in complex with Gq heterotrimer
    • Protein or peptide: Neuromedin-K receptor
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: ScFv16 nanobody
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Senktide
    • Protein or peptide: Guanine nucleotide-binding protein Gq subunit alpha

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Supramolecule #1: Senktide bound to active human neurokinin 3 receptor in complex w...

SupramoleculeName: Senktide bound to active human neurokinin 3 receptor in complex with Gq heterotrimer
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Neuromedin-K receptor

MacromoleculeName: Neuromedin-K receptor / type: protein_or_peptide / ID: 1 / Details: NK3R-pFastbac1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 44.31702 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MATLPAAETW IDGGGGVGAD AVNLTASLAA GAATGAVETG WLQLLDQAGN LSSSPSALGL PVASPAPSQP WANLTNQFVQ PSWRIALWS LAYGVVVAVA VLGNLIVIWI ILAHKRMRTV TNYFLVNLAF SDASMAAFNT LVNFIYALHS EWYFGANYCR F QNFFPITA ...String:
MATLPAAETW IDGGGGVGAD AVNLTASLAA GAATGAVETG WLQLLDQAGN LSSSPSALGL PVASPAPSQP WANLTNQFVQ PSWRIALWS LAYGVVVAVA VLGNLIVIWI ILAHKRMRTV TNYFLVNLAF SDASMAAFNT LVNFIYALHS EWYFGANYCR F QNFFPITA VFASIYSMTA IAVDRYMAII DPLKPRLSAT ATKIVIGSIW ILAFLLAFPQ CLYSKTKVMP GRTLCFVQWP EG PKQHFTY HIIVIILVYC FPLLIMGITY TIVGITLWGG EIPGDTCDKY HEQLKAKRKV VKMMIIVVMT FAICWLPYHI YFI LTAIYQ QLNRWKYIQQ VYLASFWLAM SSTMYNPIIY CCLNKRFRAG FKRAFRWCPF IKVSSYDELE LKTTRFHP

UniProtKB: Neuromedin-K receptor

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

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 41.042828 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: HMHHHHHGSL LQSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSRL LVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT RDGDVRVSRE LAGHTGYLSC C RFLDDNQI ...String:
HMHHHHHGSL LQSELDQLRQ EAEQLKNQIR DARKACADAT LSQITNNIDP VGRIQMRTRR TLRGHLAKIY AMHWGTDSRL LVSASQDGK LIIWDSYTTN KVHAIPLRSS WVMTCAYAPS GNYVACGGLD NICSIYNLKT RDGDVRVSRE LAGHTGYLSC C RFLDDNQI VTSSGDTTCA LWDIETGQQT TTFTGHTGDV MSLSLAPDTR LFVSGACDAS AKLWDVREGM CRQTFTGHES DI NAICFFP NGNAFATGSD DATCRLFDLR ADQELMTYSH DNIICGITSV SFSKSGRLLL AGYDDFNCNV WDALKADRAG VLA GHDNRV SCLGVTDDGM AVATGSWDSF LKIWNGSSGG GGSGGGGSSG VSGWRLFKKI S

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: ScFv16 nanobody

MacromoleculeName: ScFv16 nanobody / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculoides (Temminck's mouse)
Molecular weightTheoretical: 32.708473 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFAVQ LVESGGGLVQ PGGSRKLSCS ASGFAFSSFG MHWVRQAPEK GLEWVAYIS SGSGTIYYAD TVKGRFTISR DDPKNTLFLQ MTSLRSEDTA MYYCVRSIYY YGSSPFDFWG QGTTLTVSAG G GGSGGGGS ...String:
MLLVNQSHQG FNKEHTSKMV SAIVLYVLLA AAAHSAFAVQ LVESGGGLVQ PGGSRKLSCS ASGFAFSSFG MHWVRQAPEK GLEWVAYIS SGSGTIYYAD TVKGRFTISR DDPKNTLFLQ MTSLRSEDTA MYYCVRSIYY YGSSPFDFWG QGTTLTVSAG G GGSGGGGS GGGGSSDIVM TQATSSVPVT PGESVSISCR SSKSLLHSNG NTYLYWFLQR PGQSPQLLIY RMSNLASGVP DR FSGSGSG TAFTLTISRL EAEDVGVYYC MQHLEYPLTF GAGTKLELVD ENLYFQGASH HHHHHHH

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Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (cattle)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #5: Senktide

MacromoleculeName: Senktide / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 915.022 Da
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
DDFFGLMA

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Macromolecule #6: Guanine nucleotide-binding protein Gq subunit alpha

MacromoleculeName: Guanine nucleotide-binding protein Gq subunit alpha / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.694289 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGCTLSAEDK AAVERSKMIE KQLQKDKQVY RRTLRLLLLG ADNSGKSTIV KQMRIYHVNG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMIE KQLQKDKQVY RRTLRLLLLG ADNSGKSTIV KQMRIYHVNG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTSGIFETK FQVDKVNFHM FDVGAQRDER RKWIQCFNDV TAIIFVVDSS DYNRLQEALN DF DSIWNNR WLRTISVILF LNKQDLLAEK VLAGKSKIED YFPEFARYTT PEDATPEPGE DPRVTRAKYF IRKEFVDIST ASG DGRHIC YPHFTCAVDT ENARRIFNDC KDIILQMNLR EYNLV

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration1.0 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE-PROPANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: DIFFRACTION / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7rmh

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 2457160
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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