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- EMDB-36478: Focused refiment structure of NTSR1 in NTSR1-GRK2-Galpha(q) complexes -

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Basic information

Entry
Database: EMDB / ID: EMD-36478
TitleFocused refiment structure of NTSR1 in NTSR1-GRK2-Galpha(q) complexes
Map data
Sample
  • Complex: Focused refiment structure of NTSR1 in NTSR1-GRK2-Galpha(q) complexes
    • Protein or peptide: NTS
    • Protein or peptide: Neurotensin receptor type 1
  • Ligand: 2-[{2-(1-fluorocyclopropyl)-4-[4-(2-methoxyphenyl)piperidin-1-yl]quinazolin-6-yl}(methyl)amino]ethan-1-ol
KeywordsBiased signaling / SIGNALING PROTEIN
Function / homology
Function and homology information


G protein-coupled neurotensin receptor activity / inositol phosphate catabolic process / positive regulation of inhibitory postsynaptic potential / symmetric synapse / D-aspartate import across plasma membrane / positive regulation of gamma-aminobutyric acid secretion / L-glutamate import across plasma membrane / positive regulation of arachidonic acid secretion / regulation of respiratory gaseous exchange / negative regulation of release of sequestered calcium ion into cytosol ...G protein-coupled neurotensin receptor activity / inositol phosphate catabolic process / positive regulation of inhibitory postsynaptic potential / symmetric synapse / D-aspartate import across plasma membrane / positive regulation of gamma-aminobutyric acid secretion / L-glutamate import across plasma membrane / positive regulation of arachidonic acid secretion / regulation of respiratory gaseous exchange / negative regulation of release of sequestered calcium ion into cytosol / negative regulation of systemic arterial blood pressure / positive regulation of glutamate secretion / positive regulation of inositol phosphate biosynthetic process / temperature homeostasis / response to lipid / regulation of membrane depolarization / detection of temperature stimulus involved in sensory perception of pain / neuropeptide signaling pathway / Peptide ligand-binding receptors / adult locomotory behavior / positive regulation of release of sequestered calcium ion into cytosol / dendritic shaft / learning / G protein-coupled receptor activity / terminal bouton / cytoplasmic side of plasma membrane / perikaryon / chemical synaptic transmission / G alpha (q) signalling events / dendritic spine / positive regulation of apoptotic process / membrane raft / G protein-coupled receptor signaling pathway / protein-containing complex binding / positive regulation of gene expression / negative regulation of apoptotic process / Golgi apparatus / cell surface / endoplasmic reticulum / identical protein binding / plasma membrane
Similarity search - Function
Neurotensin receptor / Neurotensin type 1 receptor / 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)
Similarity search - Domain/homology
Neurotensin receptor type 1
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.02 Å
AuthorsDuan J / Liu H / Zhao F / Yuan Q / Ji Y / Xu HE
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nature / Year: 2023
Title: GPCR activation and GRK2 assembly by a biased intracellular agonist.
Authors: Jia Duan / Heng Liu / Fenghui Zhao / Qingning Yuan / Yujie Ji / Xiaoqing Cai / Xinheng He / Xinzhu Li / Junrui Li / Kai Wu / Tianyu Gao / Shengnan Zhu / Shi Lin / Ming-Wei Wang / Xi Cheng / ...Authors: Jia Duan / Heng Liu / Fenghui Zhao / Qingning Yuan / Yujie Ji / Xiaoqing Cai / Xinheng He / Xinzhu Li / Junrui Li / Kai Wu / Tianyu Gao / Shengnan Zhu / Shi Lin / Ming-Wei Wang / Xi Cheng / Wanchao Yin / Yi Jiang / Dehua Yang / H Eric Xu /
Abstract: Phosphorylation of G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) desensitizes G-protein signalling and promotes arrestin signalling, which is also modulated by biased ligands. The ...Phosphorylation of G-protein-coupled receptors (GPCRs) by GPCR kinases (GRKs) desensitizes G-protein signalling and promotes arrestin signalling, which is also modulated by biased ligands. The molecular assembly of GRKs on GPCRs and the basis of GRK-mediated biased signalling remain largely unknown owing to the weak GPCR-GRK interactions. Here we report the complex structure of neurotensin receptor 1 (NTSR1) bound to GRK2, Gα and the arrestin-biased ligand SBI-553. The density map reveals the arrangement of the intact GRK2 with the receptor, with the N-terminal helix of GRK2 docking into the open cytoplasmic pocket formed by the outward movement of the receptor transmembrane helix 6, analogous to the binding of the G protein to the receptor. SBI-553 binds at the interface between GRK2 and NTSR1 to enhance GRK2 binding. The binding mode of SBI-553 is compatible with arrestin binding but clashes with the binding of Gα protein, thus providing a mechanism for its arrestin-biased signalling capability. In sum, our structure provides a rational model for understanding the details of GPCR-GRK interactions and GRK2-mediated biased signalling.
History
DepositionJun 11, 2023-
Header (metadata) releaseAug 9, 2023-
Map releaseAug 9, 2023-
UpdateAug 30, 2023-
Current statusAug 30, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36478.png

Downloads & links

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Map

FileDownload / File: emd_36478.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.824 Å
Density
Contour LevelBy AUTHOR: 0.35
Minimum - Maximum-5.7883215 - 10.117668999999999
Average (Standard dev.)0.0018957381 (±0.04896539)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 263.68 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_36478_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_36478_half_map_1.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_36478_half_map_2.map
Projections & Slices
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Sample components

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Entire : Focused refiment structure of NTSR1 in NTSR1-GRK2-Galpha(q) complexes

EntireName: Focused refiment structure of NTSR1 in NTSR1-GRK2-Galpha(q) complexes
Components
  • Complex: Focused refiment structure of NTSR1 in NTSR1-GRK2-Galpha(q) complexes
    • Protein or peptide: NTS
    • Protein or peptide: Neurotensin receptor type 1
  • Ligand: 2-[{2-(1-fluorocyclopropyl)-4-[4-(2-methoxyphenyl)piperidin-1-yl]quinazolin-6-yl}(methyl)amino]ethan-1-ol

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Supramolecule #1: Focused refiment structure of NTSR1 in NTSR1-GRK2-Galpha(q) complexes

SupramoleculeName: Focused refiment structure of NTSR1 in NTSR1-GRK2-Galpha(q) complexes
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: NTS

MacromoleculeName: NTS / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 819.007 Da
SequenceString:
RRPYIL

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Macromolecule #2: Neurotensin receptor type 1

MacromoleculeName: Neurotensin receptor type 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.307594 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MRLNSSAPGT PGTPAADPFQ RAQAGLEEAL LAPGFGNASG NASERVLAAP SSELDVNTDI YSKVLVTAVY LALFVVGTVG NTVTAFTLA RKKSLQSLQS TVHYHLGSLA LSDLLTLLLA MPVELYNFIW VHHPWAFGDA GCRGYYFLRD ACTYATALNV A SLSVERYL ...String:
MRLNSSAPGT PGTPAADPFQ RAQAGLEEAL LAPGFGNASG NASERVLAAP SSELDVNTDI YSKVLVTAVY LALFVVGTVG NTVTAFTLA RKKSLQSLQS TVHYHLGSLA LSDLLTLLLA MPVELYNFIW VHHPWAFGDA GCRGYYFLRD ACTYATALNV A SLSVERYL AICHPFKAKT LMSRSRTKKF ISAIWLASAL LAVPMLFTMG EQNRSADGQH AGGLVCTPTI HTATVKVVIQ VN TFMSFIF PMVVISVLNT IIANKLTVMV RQAAEQGQVC TVGGEHSTFS MAIEPGRVQA LRHGVRVLRA VVIAFVVCWL PYH VRRLMF CYISDEQWTP FLYDFYHYFY MVTNALFYVS STINPILYNL VSANFRHIFL ATLACLCPVW RRRRKRPAFS RKAD SVSSN HTLSSNATRE TLY

UniProtKB: Neurotensin receptor type 1

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Macromolecule #3: 2-[{2-(1-fluorocyclopropyl)-4-[4-(2-methoxyphenyl)piperidin-1-yl]...

MacromoleculeName: 2-[{2-(1-fluorocyclopropyl)-4-[4-(2-methoxyphenyl)piperidin-1-yl]quinazolin-6-yl}(methyl)amino]ethan-1-ol
type: ligand / ID: 3 / Number of copies: 1 / Formula: SRW
Molecular weightTheoretical: 450.548 Da
Chemical component information

ChemComp-SRW:
2-[{2-(1-fluorocyclopropyl)-4-[4-(2-methoxyphenyl)piperidin-1-yl]quinazolin-6-yl}(methyl)amino]ethan-1-ol

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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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: DARK FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.02 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 474232

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