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- PDB-8jpe: Focused refinement structure of Galpha(q) in NTSR1-GRK2-Galpha(q)... -

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Basic information

Entry
Database: PDB / ID: 8jpe
TitleFocused refinement structure of Galpha(q) in NTSR1-GRK2-Galpha(q) complexes
ComponentsGuanine nucleotide-binding protein G(q) subunit alpha
KeywordsSIGNALING PROTEIN / Biased signaling
Function / homology
Function and homology information


Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / PLC beta mediated events / phospholipase C-activating dopamine receptor signaling pathway / entrainment of circadian clock / regulation of platelet activation / phototransduction, visible light / regulation of canonical Wnt signaling pathway / glutamate receptor signaling pathway / action potential ...Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion / Acetylcholine regulates insulin secretion / PLC beta mediated events / phospholipase C-activating dopamine receptor signaling pathway / entrainment of circadian clock / regulation of platelet activation / phototransduction, visible light / regulation of canonical Wnt signaling pathway / glutamate receptor signaling pathway / action potential / photoreceptor outer segment / GTPase activator activity / G protein-coupled receptor binding / negative regulation of protein kinase activity / G-protein beta/gamma-subunit complex binding / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / ADP signalling through P2Y purinoceptor 1 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / blood coagulation / heterotrimeric G-protein complex / Thrombin signalling through proteinase activated receptors (PARs) / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / nuclear membrane / G alpha (q) signalling events / protein stabilization / lysosomal membrane / GTPase activity / synapse / GTP binding / Golgi apparatus / extracellular exosome / metal ion binding / plasma membrane / cytoplasm
Similarity search - Function
G-protein alpha subunit, group Q / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
TETRAFLUOROALUMINATE ION / GUANOSINE-5'-DIPHOSPHATE / Guanine nucleotide-binding protein G(q) subunit alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.91 Å
AuthorsDuan, J. / Liu, H. / Zhao, F. / Yuan, Q. / Ji, Y. / Xu, H.E.
Funding support China, 1items
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, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 9, 2023Provider: repository / Type: Initial release
Revision 1.1Aug 16, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation_author.identifier_ORCID
Revision 1.2Aug 30, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
Q: Guanine nucleotide-binding protein G(q) subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,8534
Polymers41,2831
Non-polymers5703
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Guanine nucleotide-binding protein G(q) subunit alpha / Guanine nucleotide-binding protein alpha-q


Mass: 41282.895 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAQ, GAQ / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P50148
#2: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: GDP, energy-carrying molecule*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ALF / TETRAFLUOROALUMINATE ION


Mass: 102.975 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: AlF4 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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: Focused refinement structure of Galpha(q) in NTSR1-GRK2-Galpha(q) complexes
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
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: DARK FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 2.91 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 474232 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0022228
ELECTRON MICROSCOPYf_angle_d0.5193063
ELECTRON MICROSCOPYf_dihedral_angle_d5.417347
ELECTRON MICROSCOPYf_chiral_restr0.039378
ELECTRON MICROSCOPYf_plane_restr0.002389

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