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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 alpha (z) signalling events / Presynaptic function of Kainate receptors / Thrombin signalling through proteinase activated receptors (PARs) / Vasopressin regulates renal water homeostasis via Aquaporins / Thromboxane signalling through TP receptor / G beta:gamma signalling through PI3Kgamma / G alpha (i) signalling events / ADP signalling through P2Y purinoceptor 1 / Regulation of insulin secretion / G alpha (s) signalling events ...G alpha (z) signalling events / Presynaptic function of Kainate receptors / Thrombin signalling through proteinase activated receptors (PARs) / Vasopressin regulates renal water homeostasis via Aquaporins / Thromboxane signalling through TP receptor / G beta:gamma signalling through PI3Kgamma / G alpha (i) signalling events / ADP signalling through P2Y purinoceptor 1 / Regulation of insulin secretion / G alpha (s) signalling events / G beta:gamma signalling through PLC beta / G alpha (12/13) signalling events / G alpha (q) signalling events / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / Extra-nuclear estrogen signaling / G beta:gamma signalling through CDC42 / Adrenaline,noradrenaline inhibits insulin secretion / Prostacyclin signalling through prostacyclin receptor / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Olfactory Signaling Pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Peptide ligand-binding receptors / Inactivation, recovery and regulation of the phototransduction cascade / Activation of the phototransduction cascade / G-protein activation / Adenylate cyclase inhibitory pathway / Glucagon-type ligand receptors / Glucagon signaling in metabolic regulation / Activation of G protein gated Potassium channels / PLC beta mediated events / G protein-coupled neurotensin receptor activity / inositol phosphate catabolic process / L-glutamate import across plasma membrane / regulation of action potential / positive regulation of gamma-aminobutyric acid secretion / positive regulation of inhibitory postsynaptic potential / D-aspartate import across plasma membrane / symmetric synapse / regulation of respiratory gaseous exchange / negative regulation of systemic arterial blood pressure / regulation of cAMP-mediated signaling / cardiac muscle cell apoptotic process / G protein-coupled serotonin receptor binding / G-protein beta/gamma-subunit complex / positive regulation of inositol phosphate biosynthetic process / sensory perception of taste / cellular response to catecholamine stimulus / positive regulation of protein localization to cell cortex / temperature homeostasis / G protein-coupled acetylcholine receptor signaling pathway / negative regulation of release of sequestered calcium ion into cytosol / alkylglycerophosphoethanolamine phosphodiesterase activity / protein heterotrimerization / positive regulation of arachidonic acid secretion / rhodopsin mediated signaling pathway / positive regulation of glutamate secretion / adenylate cyclase-activating dopamine receptor signaling pathway / cell cortex region / detection of temperature stimulus involved in sensory perception of pain / photoreceptor outer segment membrane / G-protein beta-subunit binding / positive regulation of cation channel activity / neuropeptide signaling pathway / photoreceptor disc membrane / spectrin binding / regulation of mitotic spindle organization / G-protein beta/gamma-subunit complex binding / negative regulation of synaptic transmission / cellular response to forskolin / heterotrimeric G-protein complex / Wnt signaling pathway, calcium modulating pathway / GTPase activating protein binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G protein-coupled receptor activity / extracellular vesicle / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / cellular response to prostaglandin E stimulus / response to lipid / phospholipase C-activating G protein-coupled receptor signaling pathway / retina development in camera-type eye / cytoplasmic side of plasma membrane / adult locomotory behavior / GTPase binding / regulation of sensory perception of pain / photoreceptor inner segment / G protein-coupled receptor binding / response to peptide hormone / learning / dendritic shaft / positive regulation of release of sequestered calcium ion into cytosol / regulation of membrane depolarization / GDP binding / terminal bouton / cell body / midbody / lysosomal membrane / chemical synaptic transmission
WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / G-protein gamma subunit domain profile. / Trp-Asp (WD) repeats signature. / G-protein coupled receptors family 1 signature. / GGL domain / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit, group I / G-protein, beta subunit / WD40 repeat ...WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / G-protein gamma subunit domain profile. / Trp-Asp (WD) repeats signature. / G-protein coupled receptors family 1 signature. / GGL domain / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit, group I / G-protein, beta subunit / WD40 repeat / G-protein, gamma subunit / G-protein alpha subunit / 7 transmembrane receptor (rhodopsin family) / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / G-protein gamma-like domain superfamily / Neurotensin receptor / P-loop containing nucleoside triphosphate hydrolase / G-protein beta WD-40 repeat / Neurotensin type 1 receptor / G protein alpha subunit, helical insertion / WD40 repeat, conserved site / WD40-repeat-containing domain / GPCR, rhodopsin-like, 7TM / Guanine nucleotide-binding protein, beta subunit / G-protein coupled receptors family 1 profile. / G-alpha domain profile. / G-protein gamma-like domain / G protein-coupled receptor, rhodopsin-like / WD40/YVTN repeat-like-containing domain superfamily
Neurotensin receptor type 1 / 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
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 supportJapan , Denmark , United States , 6件
OrganizationGrant numberCountry
Japan Society for the Promotion of Science19H03163Japan
Novo Nordisk FoundationNNF15OC0015268Denmark
National Institutes of Health/National Human Genome Research InstituteR01GM127359United States
Japan Agency for Medical Research and Development (AMED)JP17gm5910013Japan
Japan Agency for Medical Research and Development (AMED)JP17gm0010004Japan
Japan Society for the Promotion of Science17K08264Japan
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 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
DateDeposition: May 1, 2019 / Release: Jul 10, 2019
RevisionDateData content typeProviderType
1.0Jul 10, 2019Structure modelrepositoryInitial release

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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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Protein/peptide , 3 types, 3 molecules RLD

#1: Protein/peptide 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 / Details: JMV449 from Tocris Bioscience. / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#6: Protein/peptide 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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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABC

#3: Protein/peptide 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/peptide 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/peptide 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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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-ID: ELECTRON MICROSCOPY

TypeDev idealNumber
f_bond_d0.019163
f_angle_d1.04912425
f_dihedral_angle_d10.3735408
f_chiral_restr0.0621418
f_plane_restr0.0061566

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