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- PDB-8fmz: Neurotensin receptor allosterism revealed in complex with a biase... -

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Basic information

Entry
Database: PDB / ID: 8fmz
TitleNeurotensin receptor allosterism revealed in complex with a biased allosteric modulator
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • MiniGq
  • Neurotensin receptor type 1
  • Neurotensin/neuromedin N
  • scFv16
KeywordsMEMBRANE 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 / regulation of membrane depolarization ...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 / 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 systemic arterial blood pressure / negative regulation of release of sequestered calcium ion into cytosol / G alpha (q) signalling events / positive regulation of glutamate secretion / positive regulation of inositol phosphate biosynthetic process / response to corticosterone / temperature homeostasis / response to lipid / cellular response to lithium ion / detection of temperature stimulus involved in sensory perception of pain / neuropeptide signaling pathway / response to axon injury / axon terminus / transport vesicle / response to amphetamine / cellular response to dexamethasone stimulus / blood vessel diameter maintenance / adult locomotory behavior / cellular response to nerve growth factor stimulus / positive regulation of release of sequestered calcium ion into cytosol / liver development / dendritic shaft / learning / response to cocaine / visual learning / Olfactory Signaling Pathway / Activation of the phototransduction cascade / terminal bouton / 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 / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Glucagon-type ligand receptors / cytoplasmic side of plasma membrane / 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 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / 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 / cellular response to prostaglandin E stimulus / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / response to estradiol / GTPase binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / fibroblast proliferation / G alpha (i) signalling events / G alpha (s) signalling events / G alpha (q) signalling events / perikaryon / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / dendritic spine / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor ligand activity / positive regulation of apoptotic process
Similarity search - Function
Neurotensin/neuromedin N / Neurotensin/neuromedin N precursor / Neurotensin receptor / Neurotensin type 1 receptor / 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 ...Neurotensin/neuromedin N / Neurotensin/neuromedin N precursor / Neurotensin receptor / Neurotensin type 1 receptor / 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. / 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
Similarity search - Domain/homology
Neurotensin/neuromedin N / 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
Similarity search - Component
Biological speciesEscherichia coli (E. coli)
Homo sapiens (human)
Lama glama (llama)
Rattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.59 Å
AuthorsKrumm, 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
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)0000-0002-0561-6520 United States
CitationJournal: 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
DepositionDec 26, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 29, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 19, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 30, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: MiniGq
C: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
D: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
E: scFv16
A: Neurotensin receptor type 1
F: Neurotensin/neuromedin N


Theoretical massNumber of molelcules
Total (without water)150,2856
Polymers150,2856
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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Protein , 2 types, 2 molecules BA

#1: Protein MiniGq


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


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

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Guanine nucleotide-binding protein ... , 2 types, 2 molecules CD

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


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
#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

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Antibody / Protein/peptide , 2 types, 2 molecules EF

#4: Antibody scFv16


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)
#6: Protein/peptide Neurotensin/neuromedin N


Mass: 819.007 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Rattus norvegicus (Norway rat) / References: UniProt: P20068

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Details

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: Ternary complex of NTSR1 MiniGq heterotrimer with scFv16
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.147 MDa / Experimental value: NO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5 / Details: 20mM Hepes, 0.1M NaCl, 0.00075% LMNG, 0.00075% GDN
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3200 nm / Nominal defocus min: 100 nm
Image recordingElectron dose: 44 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.59 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1086002 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0048962
ELECTRON MICROSCOPYf_angle_d0.47612156
ELECTRON MICROSCOPYf_dihedral_angle_d8.9943175
ELECTRON MICROSCOPYf_chiral_restr0.0411388
ELECTRON MICROSCOPYf_plane_restr0.0041534

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