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- PDB-6os9: human Neurotensin Receptor 1 (hNTSR1) - Gi1 Protein Complex in ca... -

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Basic information

Entry
Database: PDB / ID: 6os9
Titlehuman Neurotensin Receptor 1 (hNTSR1) - Gi1 Protein Complex in canonical conformation (C state)
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • JMV449
  • Neurotensin receptor type 1
  • scFv16
KeywordsSIGNALING PROTEIN / GPCR / G-protein / complex
Function / homology
Function and homology information


G protein-coupled neurotensin receptor activity / inositol phosphate catabolic process / regulation of action potential / L-glutamate import across plasma membrane / positive regulation of inhibitory postsynaptic potential / D-aspartate import across plasma membrane / symmetric synapse / positive regulation of gamma-aminobutyric acid secretion / negative regulation of systemic arterial blood pressure / G protein-coupled serotonin receptor binding ...G protein-coupled neurotensin receptor activity / inositol phosphate catabolic process / regulation of action potential / L-glutamate import across plasma membrane / positive regulation of inhibitory postsynaptic potential / D-aspartate import across plasma membrane / symmetric synapse / positive regulation of gamma-aminobutyric acid secretion / negative regulation of systemic arterial blood pressure / G protein-coupled serotonin receptor binding / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / negative regulation of release of sequestered calcium ion into cytosol / positive regulation of arachidonic acid secretion / positive regulation of inositol phosphate biosynthetic process / temperature homeostasis / cardiac muscle cell apoptotic process / regulation of respiratory gaseous exchange / sensory perception of taste / G-protein beta/gamma-subunit complex / cellular response to catecholamine stimulus / positive regulation of glutamate secretion / G protein-coupled acetylcholine receptor signaling pathway / detection of temperature stimulus involved in sensory perception of pain / positive regulation of cation channel activity / alkylglycerophosphoethanolamine phosphodiesterase activity / cell cortex region / rhodopsin mediated signaling pathway / adenylate cyclase-activating dopamine receptor signaling pathway / G-protein beta-subunit binding / photoreceptor outer segment membrane / regulation of mitotic spindle organization / neuropeptide signaling pathway / photoreceptor disc membrane / cellular response to forskolin / spectrin binding / negative regulation of synaptic transmission / G-protein beta/gamma-subunit complex binding / heterotrimeric G-protein complex / GTPase activating protein binding / G protein-coupled receptor activity / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / extracellular vesicle / Wnt signaling pathway, calcium modulating pathway / cellular response to prostaglandin E stimulus / cytoplasmic side of plasma membrane / phospholipase C-activating G protein-coupled receptor signaling pathway / regulation of sensory perception of pain / retina development in camera-type eye / adult locomotory behavior / GTPase binding / response to peptide hormone / G protein-coupled receptor binding / dendritic shaft / photoreceptor inner segment / response to lipid / positive regulation of release of sequestered calcium ion into cytosol / learning / GDP binding / terminal bouton / regulation of membrane depolarization / cell population proliferation / cell body / midbody / lysosomal membrane / cellular response to hypoxia / positive regulation of cytosolic calcium ion concentration / chemical synaptic transmission / platelet activation / Ras protein signal transduction / protein N-terminus binding / protein folding / perikaryon / dendritic spine / cell cycle / GTPase activity / cell division / centrosome / synapse / G protein-coupled receptor signaling pathway / positive regulation of apoptotic process / membrane raft / GTP binding / dendrite / protein-containing complex binding / signal transduction / negative regulation of apoptotic process / Golgi apparatus / magnesium ion binding / endoplasmic reticulum / cell surface / integral component of plasma membrane / mitochondrion / go:0005623: / extracellular exosome / membrane / identical protein binding / plasma membrane / nucleus
WD40/YVTN repeat-like-containing domain superfamily / Guanine nucleotide binding protein (G-protein), alpha subunit / Guanine nucleotide-binding protein, beta subunit / G-protein beta WD-40 repeat / P-loop containing nucleoside triphosphate hydrolase / GPCR, rhodopsin-like, 7TM / WD40-repeat-containing domain / G-protein gamma-like domain superfamily / WD40-repeat-containing domain superfamily / G protein-coupled receptor, rhodopsin-like ...WD40/YVTN repeat-like-containing domain superfamily / Guanine nucleotide binding protein (G-protein), alpha subunit / Guanine nucleotide-binding protein, beta subunit / G-protein beta WD-40 repeat / P-loop containing nucleoside triphosphate hydrolase / GPCR, rhodopsin-like, 7TM / WD40-repeat-containing domain / G-protein gamma-like domain superfamily / WD40-repeat-containing domain superfamily / G protein-coupled receptor, rhodopsin-like / WD40 repeat, conserved site / G-protein alpha subunit, group I / G protein alpha subunit, helical insertion / G-protein, beta subunit / Neurotensin type 1 receptor / G-protein gamma-like domain / Neurotensin receptor / WD40 repeat / G-protein, gamma subunit / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / Rhodopsin 7-helix transmembrane proteins / Rhopdopsin 7-helix transmembrane proteins / YVTN repeat-like/Quinoprotein amine dehydrogenase / Methylamine Dehydrogenase; Chain H / 7 Propeller / Irregular / Few Secondary Structures / Immunoglobulins / Immunoglobulin-like / Up-down Bundle / Sandwich / Mainly Beta / Mainly Alpha
Guanine nucleotide-binding protein G(i) subunit alpha-1 / 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 / Neurotensin receptor type 1
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsKato, H.E. / Zhang, Y. / Kobilka, B.K. / Skiniotis, G.
Funding support Japan, Denmark, United States, 6items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)19H03163 Japan
Novo Nordisk FoundationNNF15OC0015268 Denmark
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)R01GM127359 United States
Japan Agency for Medical Research and Development (AMED)JP17gm5910013 Japan
Japan Agency for Medical Research and Development (AMED)JP17gm0010004 Japan
Japan Society for the Promotion of Science (JSPS)17K08264 Japan
CitationJournal: Nature / Year: 2019
Title: Conformational transitions of a neurotensin receptor 1-G complex.
Authors: Hideaki E Kato / Yan Zhang / Hongli Hu / Carl-Mikael Suomivuori / Francois Marie Ngako Kadji / Junken Aoki / Kaavya Krishna Kumar / Rasmus Fonseca / Daniel Hilger / Weijiao Huang / Naomi R ...Authors: Hideaki E Kato / Yan Zhang / Hongli Hu / Carl-Mikael Suomivuori / Francois Marie Ngako Kadji / Junken Aoki / Kaavya Krishna Kumar / Rasmus Fonseca / Daniel Hilger / Weijiao Huang / Naomi R Latorraca / Asuka Inoue / Ron O Dror / Brian K Kobilka / Georgios Skiniotis /
Abstract: Neurotensin receptor 1 (NTSR1) is a G-protein-coupled receptor (GPCR) that engages multiple subtypes of G protein, and is involved in the regulation of blood pressure, body temperature, weight and ...Neurotensin receptor 1 (NTSR1) is a G-protein-coupled receptor (GPCR) that engages multiple subtypes of G protein, and is involved in the regulation of blood pressure, body temperature, weight and the response to pain. Here we present structures of human NTSR1 in complex with the agonist JMV449 and the heterotrimeric G protein, at a resolution of 3 Å. We identify two conformations: a canonical-state complex that is similar to recently reported GPCR-G complexes (in which the nucleotide-binding pocket adopts more flexible conformations that may facilitate nucleotide exchange), and a non-canonical state in which the G protein is rotated by about 45 degrees relative to the receptor and exhibits a more rigid nucleotide-binding pocket. In the non-canonical state, NTSR1 exhibits features of both active and inactive conformations, which suggests that the structure may represent an intermediate form along the activation pathway of G proteins. This structural information, complemented by molecular dynamics simulations and functional studies, provides insights into the complex process of G-protein activation.
Validation Report
SummaryFull reportAbout validation report
History
DepositionMay 1, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 10, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 14, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Dec 18, 2019Group: Author supporting evidence / Other / Category: atom_sites / cell / pdbx_audit_support
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] ..._atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3] / _cell.Z_PDB / _pdbx_audit_support.funding_organization

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Structure visualization

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Assembly

Deposited unit
R: Neurotensin receptor type 1
L: JMV449
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
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: scFv16


Theoretical massNumber of molelcules
Total (without water)162,8926
Polymers162,8926
Non-polymers00
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

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


Mass: 40415.031 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P63096
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37671.102 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: 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: Trichoplusia ni (cabbage looper) / References: UniProt: P59768

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

#1: Protein Neurotensin receptor type 1 / NTR1 / High-affinity levocabastine-insensitive neurotensin receptor / NTRH


Mass: 48396.734 Da / Num. of mol.: 1 / Mutation: A85L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NTSR1, NTRR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P30989
#2: Protein/peptide JMV449


Mass: 762.979 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: JMV449 from Tocris Bioscience. / Source: (synth.) synthetic construct (others)
#6: Antibody scFv16


Mass: 27784.896 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Trichoplusia ni (cabbage looper)

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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: hNTSR1-Gi1 complex in canonical conformation (C state)
Type: COMPLEX / Entity ID: 1, 2, 3, 4, 5, 6 / Source: RECOMBINANT
Molecular weightExperimental value: NO
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 FIELDBright-field microscopy
Image recordingAverage exposure time: 10 sec. / Electron dose: 75 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.13_2998: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 163333 / Symmetry type: POINT
Refine LS restraints
Refinement-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.019163
ELECTRON MICROSCOPYf_angle_d1.04912425
ELECTRON MICROSCOPYf_dihedral_angle_d10.3735408
ELECTRON MICROSCOPYf_chiral_restr0.0621418
ELECTRON MICROSCOPYf_plane_restr0.0061566

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