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- PDB-7p00: Human Neurokinin 1 receptor (NK1R) substance P Gq chimera (mGsqi)... -

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Basic information

Entry
Database: PDB / ID: 7p00
TitleHuman Neurokinin 1 receptor (NK1R) substance P Gq chimera (mGsqi) complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Antibody fragment scFv16
  • Substance P
  • Substance-P receptor
KeywordsMEMBRANE PROTEIN / Receptor / Complex / Eukaryotic protein
Function / homology
Function and homology information


substance P receptor activity / tachykinin receptor activity / positive regulation of flagellated sperm motility / aggressive behavior / Tachykinin receptors bind tachykinins / sperm ejaculation / positive regulation of uterine smooth muscle contraction / positive regulation of synaptic transmission, cholinergic / detection of abiotic stimulus / operant conditioning ...substance P receptor activity / tachykinin receptor activity / positive regulation of flagellated sperm motility / aggressive behavior / Tachykinin receptors bind tachykinins / sperm ejaculation / positive regulation of uterine smooth muscle contraction / positive regulation of synaptic transmission, cholinergic / detection of abiotic stimulus / operant conditioning / positive regulation of lymphocyte proliferation / tachykinin receptor signaling pathway / response to ozone / sperm head / positive regulation of action potential / response to auditory stimulus / positive regulation of blood pressure / smooth muscle contraction involved in micturition / regulation of smooth muscle cell proliferation / positive regulation of vascular permeability / positive regulation of hormone secretion / positive regulation of ossification / regulation of smooth muscle cell migration / positive regulation of leukocyte migration / eating behavior / positive regulation of vasoconstriction / behavioral response to pain / angiotensin-mediated drinking behavior / associative learning / positive regulation of epithelial cell migration / response to electrical stimulus / long-term memory / sperm flagellum / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / Adenylate cyclase inhibitory pathway / T cell migration / positive regulation of stress fiber assembly / D2 dopamine receptor binding / response to prostaglandin E / adenylate cyclase regulator activity / sperm midpiece / G protein-coupled serotonin receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / cellular response to forskolin / response to progesterone / regulation of mitotic spindle organization / positive regulation of epithelial cell proliferation / positive regulation of synaptic transmission, GABAergic / response to nicotine / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / G protein-coupled receptor binding / response to peptide hormone / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / 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 / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / 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 / 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 / GDP binding / 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 / response to estradiol / Inactivation, recovery and regulation of the phototransduction cascade / Cargo recognition for clathrin-mediated endocytosis / 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 / Thrombin signalling through proteinase activated receptors (PARs)
Similarity search - Function
Neurokinin NK1 receptor / Neurokinin receptor / G-protein alpha subunit, group S / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / 7 Propeller / Methylamine Dehydrogenase; Chain H / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit ...Neurokinin NK1 receptor / Neurokinin receptor / G-protein alpha subunit, group S / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / 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 / 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 / P-loop containing nucleotide triphosphate hydrolases / 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 / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
CHOLESTEROL / Guanine nucleotide-binding protein G(s) subunit alpha / Substance-P receptor / 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 speciesMus musculus (house mouse)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.71 Å
AuthorsThom, C. / Ehrenmann, J. / Vacca, S. / Waltenspuhl, Y. / Schoppe, J. / Medalia, O. / Pluckthun, A.
Funding support Switzerland, 2items
OrganizationGrant numberCountry
Swiss National Science Foundation31003A_182334 Switzerland
European Research Council (ERC)810057-HighResCells Switzerland
CitationJournal: Sci Adv / Year: 2021
Title: Structures of neurokinin 1 receptor in complex with G and G proteins reveal substance P binding mode and unique activation features.
Authors: Cristian Thom / Janosch Ehrenmann / Santiago Vacca / Yann Waltenspühl / Jendrik Schöppe / Ohad Medalia / Andreas Plückthun /
Abstract: The neurokinin 1 receptor (NKR) is involved in inflammation and pain transmission. This pathophysiologically important G protein–coupled receptor is predominantly activated by its cognate agonist ...The neurokinin 1 receptor (NKR) is involved in inflammation and pain transmission. This pathophysiologically important G protein–coupled receptor is predominantly activated by its cognate agonist substance P (SP) but also by the closely related neurokinins A and B. Here, we report cryo–electron microscopy structures of SP-bound NKR in complex with its primary downstream signal mediators, G and G. Our structures reveal how a polar network at the extracellular, solvent-exposed receptor surface shapes the orthosteric pocket and that NKR adopts a noncanonical active-state conformation with an interface for G protein binding, which is distinct from previously reported structures. Detailed comparisons with antagonist-bound NKR crystal structures reveal that insurmountable antagonists induce a distinct and long-lasting receptor conformation that sterically blocks SP binding. Together, our structures provide important structural insights into ligand and G protein promiscuity, the lack of basal signaling, and agonist- and antagonist-induced conformations in the neurokinin receptor family.
History
DepositionJun 29, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 15, 2021Provider: repository / Type: Initial release
Revision 1.0Dec 15, 2021Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Dec 15, 2021Data content type: Additional map / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Dec 15, 2021Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 15, 2021Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Dec 15, 2021Data content type: Additional map / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Dec 15, 2021Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 15, 2021Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Jul 2, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 2, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

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Assembly

Deposited unit
H: Antibody fragment scFv16
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
A: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
R: Substance-P receptor
P: Substance P
hetero molecules


Theoretical massNumber of molelcules
Total (without water)153,6157
Polymers153,2296
Non-polymers3871
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area13270 Å2
ΔGint-75 kcal/mol
Surface area48330 Å2
MethodPISA

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Components

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

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


Mass: 39086.641 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
#4: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-inhibiting G alpha protein


Mass: 28304.219 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1, GNAS / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096, UniProt: A0A590UJY2

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Antibody / Protein / Protein/peptide / Non-polymers , 4 types, 4 molecules HRP

#1: Antibody Antibody fragment scFv16


Mass: 32409.229 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)
#5: Protein Substance-P receptor / SPR / NK-1 receptor / NK-1R / Tachykinin receptor 1


Mass: 44218.668 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TACR1, NK1R, TAC1R / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P25103
#6: Protein/peptide Substance P


Mass: 1348.637 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#7: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O

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Details

Has ligand of interestN
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: NK1R in complex with Substance P, heterotrimeric mini-Gq chimera (Gsqi) and scFv16
Type: COMPLEX / Entity ID: #1-#6 / 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
Specimen supportGrid material: GOLD / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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 magnification: 130000 X / Nominal defocus max: 2400 nm / Calibrated defocus min: 800 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 62.51 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.1_4122: / Classification: refinement
EM software
IDNameVersionCategory
1cryoSPARC3.0.1particle selection
4Gctf1.06CTF correction
8PHENIXmodel refinement
10cryoSPARC3.0.1initial Euler assignment
11cryoSPARC3.0.1final Euler assignment
13cryoSPARC3.0.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 3511990
3D reconstructionResolution: 2.71 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 558058 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0129321
ELECTRON MICROSCOPYf_angle_d1.67912654
ELECTRON MICROSCOPYf_dihedral_angle_d12.4463334
ELECTRON MICROSCOPYf_chiral_restr0.1151415
ELECTRON MICROSCOPYf_plane_restr0.0061596

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