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Yorodumi- PDB-8fmz: Neurotensin receptor allosterism revealed in complex with a biase... -
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-Basic information
Entry | Database: PDB / ID: 8fmz | ||||||
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Title | Neurotensin receptor allosterism revealed in complex with a biased allosteric modulator | ||||||
Components |
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Keywords | MEMBRANE PROTEIN / GPCR / neurotensin receptor / allosterism / SBI-553 | ||||||
Function / homology | Function and homology information response to antipsychotic drug / Peptide ligand-binding receptors / neuropeptide receptor binding / G protein-coupled neurotensin receptor activity / inositol phosphate catabolic process / symmetric synapse / response to mineralocorticoid / D-aspartate import across plasma membrane / positive regulation of gamma-aminobutyric acid secretion / response to lipid ...response to antipsychotic drug / Peptide ligand-binding receptors / neuropeptide receptor binding / G protein-coupled neurotensin receptor activity / inositol phosphate catabolic process / symmetric synapse / response to mineralocorticoid / D-aspartate import across plasma membrane / positive regulation of gamma-aminobutyric acid secretion / response to lipid / regulation of membrane depolarization / positive regulation of arachidonate secretion / L-glutamate import across plasma membrane / neuron spine / regulation of respiratory gaseous exchange / positive regulation of inhibitory postsynaptic potential / neuropeptide hormone activity / hyperosmotic response / digestive tract development / negative regulation of release of sequestered calcium ion into cytosol / negative regulation of systemic arterial blood pressure / G alpha (q) signalling events / positive regulation of glutamate secretion / positive regulation of inositol phosphate biosynthetic process / temperature homeostasis / response to corticosterone / cellular response to lithium ion / detection of temperature stimulus involved in sensory perception of pain / neuropeptide signaling pathway / response to axon injury / cellular response to dexamethasone stimulus / axon terminus / transport vesicle / response to amphetamine / blood vessel diameter maintenance / adult locomotory behavior / positive regulation of release of sequestered calcium ion into cytosol / cellular response to nerve growth factor stimulus / liver development / learning / response to cocaine / dendritic shaft / visual learning / 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 / terminal bouton / 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 / cytoplasmic side of plasma membrane / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / response to estradiol / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / perikaryon / Extra-nuclear estrogen signaling / cell population proliferation / dendritic spine / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor ligand activity / membrane raft Similarity search - Function | ||||||
Biological species | Escherichia coli (E. coli) Homo sapiens (human) Lama glama (llama) Rattus norvegicus (Norway rat) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.59 Å | ||||||
Authors | Krumm, B.E. / Diberto, J.F. / Olsen, R.H.J. / Kang, H. / Slocum, S.T. / Zhang, S. / Strachan, R.T. / Fay, J.F. / Roth, B.L. | ||||||
Funding support | United States, 1items
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Citation | Journal: Biochemistry / Year: 2023 Title: Neurotensin Receptor Allosterism Revealed in Complex with a Biased Allosteric Modulator. Authors: Brian E Krumm / Jeffrey F DiBerto / Reid H J Olsen / Hye Jin Kang / Samuel T Slocum / Shicheng Zhang / Ryan T Strachan / Xi-Ping Huang / Lauren M Slosky / Anthony B Pinkerton / Lawrence S ...Authors: Brian E Krumm / Jeffrey F DiBerto / Reid H J Olsen / Hye Jin Kang / Samuel T Slocum / Shicheng Zhang / Ryan T Strachan / Xi-Ping Huang / Lauren M Slosky / Anthony B Pinkerton / Lawrence S Barak / Marc G Caron / Terry Kenakin / Jonathan F Fay / Bryan L Roth / Abstract: The NTSR1 neurotensin receptor (NTSR1) is a G protein-coupled receptor (GPCR) found in the brain and peripheral tissues with neurotensin (NTS) being its endogenous peptide ligand. In the brain, NTS ...The NTSR1 neurotensin receptor (NTSR1) is a G protein-coupled receptor (GPCR) found in the brain and peripheral tissues with neurotensin (NTS) being its endogenous peptide ligand. In the brain, NTS modulates dopamine neuronal activity, induces opioid-independent analgesia, and regulates food intake. Recent studies indicate that biasing NTSR1 toward β-arrestin signaling can attenuate the actions of psychostimulants and other drugs of abuse. Here, we provide the cryoEM structures of NTSR1 ternary complexes with heterotrimeric Gq and GoA with and without the brain-penetrant small-molecule SBI-553. In functional studies, we discovered that SBI-553 displays complex allosteric actions exemplified by negative allosteric modulation for G proteins that are Gα subunit selective and positive allosteric modulation and agonism for β-arrestin translocation at NTSR1. Detailed structural analysis of the allosteric binding site illuminated the structural determinants for biased allosteric modulation of SBI-553 on NTSR1. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8fmz.cif.gz | 229.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8fmz.ent.gz | 180.6 KB | Display | PDB format |
PDBx/mmJSON format | 8fmz.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8fmz_validation.pdf.gz | 1.2 MB | Display | wwPDB validaton report |
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Full document | 8fmz_full_validation.pdf.gz | 1.2 MB | Display | |
Data in XML | 8fmz_validation.xml.gz | 39.8 KB | Display | |
Data in CIF | 8fmz_validation.cif.gz | 59.2 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/fm/8fmz ftp://data.pdbj.org/pub/pdb/validation_reports/fm/8fmz | HTTPS FTP |
-Related structure data
Related structure data | 29301MC 8fn0C 8fn1C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 2 types, 2 molecules BA
#1: Protein | Mass: 28084.832 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Escherichia coli (E. coli) / Production host: Spodoptera frugiperda (fall armyworm) |
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#5: Protein | Mass: 45432.668 Da / Num. of mol.: 1 / Mutation: A86L, G215A, V360A Source method: isolated from a genetically manipulated source Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Ntsr1, Ntsr / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P20789 |
-Guanine nucleotide-binding protein ... , 2 types, 2 molecules CD
#2: Protein | Mass: 39418.086 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 |
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#3: Protein | 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 |
-Antibody / Protein/peptide , 2 types, 2 molecules EF
#4: Antibody | Mass: 28668.922 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Lama glama (llama) / Production host: Spodoptera frugiperda (fall armyworm) |
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#6: Protein/peptide | Mass: 819.007 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Rattus norvegicus (Norway rat) / References: UniProt: P20068 |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Ternary complex of NTSR1 MiniGq heterotrimer with scFv16 Type: COMPLEX / Entity ID: all / Source: RECOMBINANT |
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Molecular weight | Value: 0.147 MDa / Experimental value: NO |
Source (natural) | Organism: Rattus norvegicus (Norway rat) |
Source (recombinant) | Organism: Spodoptera frugiperda (fall armyworm) |
Buffer solution | pH: 7.5 / Details: 20mM Hepes, 0.1M NaCl, 0.00075% LMNG, 0.00075% GDN |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE-PROPANE |
-Electron microscopy imaging
Experimental equipment | Model: Talos Arctica / Image courtesy: FEI Company |
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Microscopy | Model: FEI TALOS ARCTICA |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: OTHER |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 3200 nm / Nominal defocus min: 100 nm |
Image recording | Electron dose: 44 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
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3D reconstruction | Resolution: 2.59 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1086002 / Symmetry type: POINT | ||||||||||||||||||||||||
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