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Entry
Database: EMDB / ID: EMD-29301
TitleNeurotensin receptor allosterism revealed in complex with a biased allosteric modulator
Map dataNeurotensin receptor allosterism revealed in complex with a biased allosteric modulator
Sample
  • Complex: Ternary complex of NTSR1 MiniGq heterotrimer with scFv16
    • Protein or peptide: MiniGq
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: scFv16
    • Protein or peptide: Neurotensin receptor type 1
    • Protein or peptide: Neurotensin/neuromedin N
KeywordsGPCR / neurotensin receptor / allosterism / SBI-553 / MEMBRANE PROTEIN
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 / neuron spine / L-glutamate import across plasma membrane / regulation of respiratory gaseous exchange / positive regulation of inhibitory postsynaptic potential / neuropeptide hormone activity / hyperosmotic response / negative regulation of systemic arterial blood pressure / positive regulation of glutamate secretion / negative regulation of release of sequestered calcium ion into cytosol / digestive tract development / G alpha (q) signalling events / response to corticosterone / positive regulation of inositol phosphate biosynthetic process / response to lipid / cellular response to lithium ion / temperature homeostasis / detection of temperature stimulus involved in sensory perception of pain / response to axon injury / neuropeptide signaling pathway / transport vesicle / axon terminus / response to amphetamine / cellular response to dexamethasone stimulus / positive regulation of release of sequestered calcium ion into cytosol / dendritic shaft / blood vessel diameter maintenance / liver development / adult locomotory behavior / learning / response to cocaine / cellular response to nerve growth factor stimulus / terminal bouton / visual learning / cytoplasmic side of plasma membrane / 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 / 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 / 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 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / 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 / response to estradiol / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / Ca2+ pathway / retina development in camera-type eye / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / dendritic spine / perikaryon / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / G protein-coupled receptor signaling pathway
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. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / 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 speciesRattus norvegicus (Norway rat) / Escherichia coli (E. coli) / Homo sapiens (human) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.59 Å
AuthorsKrumm BE / Diberto JF / Olsen RHJ / Kang H / Slocum ST / Zhang S / Strachan RT / Fay JF / Roth BL
Funding support United States, 1 items
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, 2022-
Header (metadata) releaseMar 29, 2023-
Map releaseMar 29, 2023-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29301.png

Downloads & links

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Map

FileDownload / File: emd_29301.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationNeurotensin receptor allosterism revealed in complex with a biased allosteric modulator
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.88 Å/pix.
x 256 pix.
= 225.28 Å		0.88 Å/pix.
x 256 pix.
= 225.28 Å		0.88 Å/pix.
x 256 pix.
= 225.28 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.88 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy EMDB: 0.7
Minimum - Maximum-5.0509324 - 7.367277
Average (Standard dev.)-0.0010486983 (±0.15889283)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 225.28 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map 1

Fileemd_29301_half_map_1.map
AnnotationHalf Map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map 2

Fileemd_29301_half_map_2.map
AnnotationHalf Map 2
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Ternary complex of NTSR1 MiniGq heterotrimer with scFv16

EntireName: Ternary complex of NTSR1 MiniGq heterotrimer with scFv16
Components
  • Complex: Ternary complex of NTSR1 MiniGq heterotrimer with scFv16
    • Protein or peptide: MiniGq
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: scFv16
    • Protein or peptide: Neurotensin receptor type 1
    • Protein or peptide: Neurotensin/neuromedin N

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Supramolecule #1: Ternary complex of NTSR1 MiniGq heterotrimer with scFv16

SupramoleculeName: Ternary complex of NTSR1 MiniGq heterotrimer with scFv16
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 147 KDa

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Macromolecule #1: MiniGq

MacromoleculeName: MiniGq / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Escherichia coli (E. coli)
Molecular weightTheoretical: 28.084832 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA ...String:
MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA RYTTPEDATP EPGEDPRVTR AKYFIRKEFV DISTASGDGR HICYPHFTCA VDTENARRIF NDCKDIILQM NL REYNLV

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

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.418086 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHHHHHHLEV LFQGPGSSGS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR ...String:
MHHHHHHLEV LFQGPGSSGS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR FLDDNQIVTS SGDTTCALWD IETGQQTTTF TGHTGDVMSL SLAPDTRLFV SGACDASAKL WDVREGMCRQ TF TGHESDI NAICFFPNGN AFATGSDDAT CRLFDLRADQ ELMTYSHDNI ICGITSVSFS KSGRLLLAGY DDFNCNVWDA LKA DRAGVL AGHDNRVSCL GVTDDGMAVA TGSWDSFLKI WN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #4: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 28.668922 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL KAAALEVLFQ GPHHHHHHHH

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Macromolecule #5: Neurotensin receptor type 1

MacromoleculeName: Neurotensin receptor type 1 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 45.432668 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHHHHHHHHH HSDLEVLFQG PLGSGAPTSE SDTAGPNSDL DVNTDIYSKV LVTAIYLALF VVGTVGNSVT LFTLARKKSL QSLQSTVHY HLGSLALSDL LILLLAMPVE LYNFIWVHHP WAFGDAGCRG YYFLRDACTY ATALNVASLS VERYLAICHP F KAKTLMSR ...String:
MHHHHHHHHH HSDLEVLFQG PLGSGAPTSE SDTAGPNSDL DVNTDIYSKV LVTAIYLALF VVGTVGNSVT LFTLARKKSL QSLQSTVHY HLGSLALSDL LILLLAMPVE LYNFIWVHHP WAFGDAGCRG YYFLRDACTY ATALNVASLS VERYLAICHP F KAKTLMSR SRTKKFISAI WLASALLAIP MLFTMGLQNR SADGTHPGGL VCTPIVDTAT VKVVIQVNTF MSFLFPMLVI SI LNTVIAN KLTVMVHQAA EQGRVCTVGT HNGLEHSTFN MTIEPGRVQA LRHGVLVLRA VVIAFVVCWL PYHVRRLMFC YIS DEQWTT FLFDFYHYFY MLTNALFYAS SAINPILYNL VSANFRQVFL STLACLCPGW RHRRKKRPTF SRKPNSMSSN HAFS TSATR

UniProtKB: Neurotensin receptor type 1

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Macromolecule #6: Neurotensin/neuromedin N

MacromoleculeName: Neurotensin/neuromedin N / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 819.007 Da
SequenceString:
RRPYIL

UniProtKB: Neurotensin/neuromedin N

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5 / Details: 20mM Hepes, 0.1M NaCl, 0.00075% LMNG, 0.00075% GDN
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 44.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.2 µm / Nominal defocus min: 0.1 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

4xes

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.59 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1086002
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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