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- PDB-7rmi: SP6-11 biased agonist bound to active human neurokinin 1 receptor... -

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Basic information

Entry
Database: PDB / ID: 7rmi
TitleSP6-11 biased agonist bound to active human neurokinin 1 receptor in complex with miniGs/q70
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Nanobody 35
  • Substance P 6-11
  • Substance-P receptor
KeywordsSIGNALING PROTEIN/MEMBRANE PROTEIN / Substance P / G protein / GPCR / Neurokinin / Tachykinin / SIGNALING PROTEIN / SIGNALING PROTEIN-MEMBRANE PROTEIN complex
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 / positive regulation of uterine smooth muscle contraction / positive regulation of synaptic transmission, cholinergic / detection of abiotic stimulus / operant conditioning / positive regulation of lymphocyte proliferation ...substance P receptor activity / tachykinin receptor activity / positive regulation of flagellated sperm motility / aggressive behavior / Tachykinin receptors bind tachykinins / positive regulation of uterine smooth muscle contraction / positive regulation of synaptic transmission, cholinergic / detection of abiotic stimulus / operant conditioning / positive regulation of lymphocyte proliferation / sperm ejaculation / tachykinin receptor signaling pathway / response to ozone / sperm head / positive regulation of action potential / response to auditory stimulus / regulation of smooth muscle cell proliferation / smooth muscle contraction involved in micturition / positive regulation of hormone secretion / positive regulation of blood pressure / positive regulation of vascular permeability / positive regulation of ossification / regulation of smooth muscle cell migration / positive regulation of leukocyte migration / eating behavior / associative learning / behavioral response to pain / PKA activation in glucagon signalling / angiotensin-mediated drinking behavior / sperm flagellum / hair follicle placode formation / positive regulation of epithelial cell migration / developmental growth / D1 dopamine receptor binding / long-term memory / intracellular transport / renal water homeostasis / Hedgehog 'off' state / response to electrical stimulus / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / positive regulation of stress fiber assembly / positive regulation of vasoconstriction / sperm midpiece / regulation of insulin secretion / cellular response to glucagon stimulus / adenylate cyclase activator activity / positive regulation of epithelial cell proliferation / trans-Golgi network membrane / response to progesterone / positive regulation of synaptic transmission, GABAergic / response to nicotine / negative regulation of inflammatory response to antigenic stimulus / bone development / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / platelet aggregation / cognition / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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 / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / 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 / sensory perception of smell / 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 / Cargo recognition for clathrin-mediated endocytosis / extracellular vesicle / response to estradiol / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / Clathrin-mediated endocytosis
Similarity search - Function
Neurokinin NK1 receptor / Neurokinin receptor / G-protein alpha subunit, group S / 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. ...Neurokinin NK1 receptor / Neurokinin receptor / G-protein alpha subunit, group S / 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. / P-loop containing nucleotide triphosphate hydrolases / 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 / Immunoglobulins / Immunoglobulin-like / Sandwich / P-loop containing nucleoside triphosphate hydrolase / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
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(s) subunit alpha isoforms short
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsHarris, J.A. / Faust, B. / Gondin, A.B. / Daemgen, M.A. / Suomivuori, C.M. / Veldhuis, N.A. / Cheng, Y. / Dror, R.O. / Thal, D. / Manglik, A.
Funding support United States, Australia, 11items
OrganizationGrant numberCountry
National Institutes of Health/Office of the DirectorDP5OD023048 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM127359 United States
National Health and Medical Research Council (NHMRC, Australia)APP1138448 Australia
National Health and Medical Research Council (NHMRC, Australia)APP1196951 Australia
Australian Research Council (ARC)DE170100152 Australia
National Science Foundation (NSF, United States)2034836 United States
Human Frontier Science Program (HFSP)LT000916/2018-L United States
National Institutes of Health/Office of the DirectorS10OD020054 United States
National Institutes of Health/Office of the DirectorS10OD020054 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)U24 GM129541 United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nat Chem Biol / Year: 2022
Title: Selective G protein signaling driven by substance P-neurokinin receptor dynamics.
Authors: Julian A Harris / Bryan Faust / Arisbel B Gondin / Marc André Dämgen / Carl-Mikael Suomivuori / Nicholas A Veldhuis / Yifan Cheng / Ron O Dror / David M Thal / Aashish Manglik /
Abstract: The neuropeptide substance P (SP) is important in pain and inflammation. SP activates the neurokinin-1 receptor (NK1R) to signal via G and G proteins. Neurokinin A also activates NK1R, but leads to ...The neuropeptide substance P (SP) is important in pain and inflammation. SP activates the neurokinin-1 receptor (NK1R) to signal via G and G proteins. Neurokinin A also activates NK1R, but leads to selective G signaling. How two stimuli yield distinct G protein signaling at the same G protein-coupled receptor remains unclear. We determined cryogenic-electron microscopy structures of active NK1R bound to SP or the G-biased peptide SP6-11. Peptide interactions deep within NK1R are critical for receptor activation. Conversely, interactions between SP and NK1R extracellular loops are required for potent G signaling but not G signaling. Molecular dynamics simulations showed that these superficial contacts restrict SP flexibility. SP6-11, which lacks these interactions, is dynamic while bound to NK1R. Structural dynamics of NK1R agonists therefore depend on interactions with the receptor extracellular loops and regulate G protein signaling selectivity. Similar interactions between other neuropeptides and their cognate receptors may tune intracellular signaling.
History
DepositionJul 27, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 3, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 10, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Jan 5, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year
Revision 1.3Nov 13, 2024Group: Data collection / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_3d_fitting_list / em_admin / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature
Item: _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id ..._em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, with certain residues mutated to match Guanine nucleotide-binding protein G(q) subunit
R: Substance-P receptor
S: Substance P 6-11
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
N: Nanobody 35


Theoretical massNumber of molelcules
Total (without water)138,4826
Polymers138,4826
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

#1: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, with certain residues mutated to match Guanine nucleotide-binding protein G(q) subunit / miniGs/q70 / Adenylate cyclase-stimulating G alpha protein


Mass: 26450.961 Da / Num. of mol.: 1
Mutation: the Gsq/70 construct has mutations to make it a mimetic of the Galphaq protein (on a Gs framework)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Homo sapiens (human) / References: UniProt: P63092
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 40786.566 Da / Num. of mol.: 1
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
#5: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7563.750 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

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

#2: Protein Substance-P receptor / SPR / NK-1 receptor / NK-1R / Tachykinin receptor 1


Mass: 47542.867 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: Homo sapiens (human) / References: UniProt: P25103
#3: Protein/peptide Substance P 6-11


Mass: 739.905 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#6: Antibody Nanobody 35


Mass: 15398.067 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)

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Details

Has ligand of interestY
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

Component
IDNameTypeEntity IDParent-IDSource
1Substance P bound to Neurokinin 1 receptor-miniGs/q70 complexCOMPLEXall0MULTIPLE SOURCES
2Guanine nucleotide-binding protein G(s)/G(q) subunit alpha hybridCOMPLEX#11RECOMBINANT
3Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1/gamma-2COMPLEX#4-#51RECOMBINANT
4Substance-P receptorCOMPLEX#21RECOMBINANT
5Substance P 6-11COMPLEX#31SYNTHETIC
6Nanobody 35COMPLEX#61RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
34Homo sapiens (human)9606
45synthetic construct (others)32630
56Lama glama (llama)9844
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Trichoplusia ni (cabbage looper)7111
34Homo sapiens (human)9606
46Escherichia coli (E. coli)562
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / 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 / Alignment procedure: COMA FREE
Image recordingAverage exposure time: 5.9 sec. / Electron dose: 67 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.19.2_4158refinement
PHENIX1.19.2_4158refinement
EM software
IDNameVersionCategoryDetails
1cryoSPARCparticle selectionTemplate Picker
2SerialEM3.8image acquisition
4cryoSPARCCTF correctionPatch CTF
7PHENIXmodel fitting
9cryoSPARCinitial Euler assignment
10cisTEMfinal Euler assignment
11RELIONclassification
12cisTEM3D reconstruction
13PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 4135583
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 59926 / Symmetry type: POINT
Atomic model buildingSpace: REAL
Atomic model buildingPDB-ID: 6HLP

6hlp


Accession code: 6HLP / Source name: PDB / Type: experimental model
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 50.06 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00427376
ELECTRON MICROSCOPYf_angle_d0.842210067
ELECTRON MICROSCOPYf_chiral_restr0.05251177
ELECTRON MICROSCOPYf_plane_restr0.00661255
ELECTRON MICROSCOPYf_dihedral_angle_d12.68132426

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