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- PDB-6li1: Crystal structure of GPR52 ligand free form with flavodoxin fusion -

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Basic information

Entry
Database: PDB / ID: 6li1
TitleCrystal structure of GPR52 ligand free form with flavodoxin fusion
ComponentsChimera of G-protein coupled receptor 52 and Flavodoxin
KeywordsMEMBRANE PROTEIN / Human GPR52 receptor / Class A / orphan GPCR / apo form / flavodoxin / LCP
Function / homology
Function and homology information


G protein-coupled photoreceptor activity / cellular response to light stimulus / phototransduction / locomotory behavior / G protein-coupled receptor activity / FMN binding / electron transfer activity / response to xenobiotic stimulus / G protein-coupled receptor signaling pathway / plasma membrane
Similarity search - Function
Flavodoxin, short chain / Flavodoxin, conserved site / Flavodoxin signature. / Flavodoxin-like / Flavodoxin / Flavodoxin-like domain profile. / Flavodoxin/nitric oxide synthase / Flavoprotein-like superfamily / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like ...Flavodoxin, short chain / Flavodoxin, conserved site / Flavodoxin signature. / Flavodoxin-like / Flavodoxin / Flavodoxin-like domain profile. / Flavodoxin/nitric oxide synthase / Flavoprotein-like superfamily / 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
FLAVIN MONONUCLEOTIDE / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / DI(HYDROXYETHYL)ETHER / TRIETHYLENE GLYCOL / Flavodoxin / G-protein coupled receptor 52
Similarity search - Component
Biological speciesHomo sapiens (human)
Desulfovibrio vulgaris str. Hildenborough (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsLuo, Z.P. / Lin, X. / Xu, F. / Han, G.W.
Funding support China, 1items
OrganizationGrant numberCountry
National Science Foundation (NSF, China) China
CitationJournal: Nature / Year: 2020
Title: Structural basis of ligand recognition and self-activation of orphan GPR52.
Authors: Xi Lin / Mingyue Li / Niandong Wang / Yiran Wu / Zhipu Luo / Shimeng Guo / Gye-Won Han / Shaobai Li / Yang Yue / Xiaohu Wei / Xin Xie / Yong Chen / Suwen Zhao / Jian Wu / Ming Lei / Fei Xu /
Abstract: GPR52 is a class-A orphan G-protein-coupled receptor that is highly expressed in the brain and represents a promising therapeutic target for the treatment of Huntington's disease and several ...GPR52 is a class-A orphan G-protein-coupled receptor that is highly expressed in the brain and represents a promising therapeutic target for the treatment of Huntington's disease and several psychiatric disorders. Pathological malfunction of GPR52 signalling occurs primarily through the heterotrimeric G protein, but it is unclear how GPR52 and G couple for signal transduction and whether a native ligand or other activating input is required. Here we present the high-resolution structures of human GPR52 in three states: a ligand-free state, a G-coupled self-activation state and a potential allosteric ligand-bound state. Together, our structures reveal that extracellular loop 2 occupies the orthosteric binding pocket and operates as a built-in agonist, conferring an intrinsically high level of basal activity to GPR52. A fully active state is achieved when G is coupled to GPR52 in the absence of an external agonist. The receptor also features a side pocket for ligand binding. These insights into the structure and function of GPR52 could improve our understanding of other self-activated GPCRs, enable the identification of endogenous and tool ligands, and guide drug discovery efforts that target GPR52.
History
DepositionDec 10, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 26, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 4, 2020Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Mar 18, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Apr 3, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Chimera of G-protein coupled receptor 52 and Flavodoxin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,5916
Polymers50,1651
Non-polymers1,4265
Water1267
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area790 Å2
ΔGint-6 kcal/mol
Surface area20440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.648, 79.891, 148.304
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Chimera of G-protein coupled receptor 52 and Flavodoxin


Mass: 50164.812 Da / Num. of mol.: 1 / Mutation: A130W,Y1098W,W278Q,C314P,S318A,N321D,V323T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Desulfovibrio vulgaris str. Hildenborough (bacteria)
Gene: GPR52, DVU_2680 / Strain: Hildenborough / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9Y2T5, UniProt: P00323

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Non-polymers , 5 types, 12 molecules

#2: Chemical ChemComp-OLC / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / 1-Oleoyl-R-glycerol


Mass: 356.540 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H40O4
#3: Chemical ChemComp-FMN / FLAVIN MONONUCLEOTIDE / RIBOFLAVIN MONOPHOSPHATE


Mass: 456.344 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H21N4O9P
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#5: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C6H14O4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 7 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.98 Å3/Da / Density % sol: 69.09 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase / pH: 5
Details: 0.1 M potassium acetate, 0.1 M sodium citrate pH 5.0, and 30% PEG400

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 1, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.9→50 Å / Num. obs: 18312 / % possible obs: 97.6 % / Redundancy: 9.2 % / CC1/2: 0.991 / Rmerge(I) obs: 0.235 / Net I/σ(I): 11.8
Reflection shellResolution: 2.9→3 Å / Rmerge(I) obs: 2.748 / Mean I/σ(I) obs: 0.98 / Num. unique obs: 1810 / CC1/2: 0.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0253refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: Rosetta modelling

Resolution: 2.9→28.43 Å / Cor.coef. Fo:Fc: 0.917 / Cor.coef. Fo:Fc free: 0.915 / SU B: 21.26 / SU ML: 0.367 / Cross valid method: THROUGHOUT / ESU R: 0.811 / ESU R Free: 0.364 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS There are some unknown densities located near N5 atom of FMN in a chain. This was not been modelled.
RfactorNum. reflection% reflectionSelection details
Rfree0.26677 912 5.2 %RANDOM
Rwork0.24427 ---
obs0.24548 16462 95.56 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 78.363 Å2
Baniso -1Baniso -2Baniso -3
1-0.98 Å20 Å20 Å2
2---0.66 Å20 Å2
3----0.32 Å2
Refinement stepCycle: 1 / Resolution: 2.9→28.43 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3339 0 72 7 3418
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0133495
X-RAY DIFFRACTIONr_bond_other_d0.0080.0173141
X-RAY DIFFRACTIONr_angle_refined_deg1.5411.6474764
X-RAY DIFFRACTIONr_angle_other_deg0.811.587207
X-RAY DIFFRACTIONr_dihedral_angle_1_deg3.425440
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.65720.867150
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.04615493
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.311518
X-RAY DIFFRACTIONr_chiral_restr0.0880.2477
X-RAY DIFFRACTIONr_gen_planes_refined0.0410.023911
X-RAY DIFFRACTIONr_gen_planes_other0.0340.02805
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it14.71116.9651763
X-RAY DIFFRACTIONr_mcbond_other14.70816.9591762
X-RAY DIFFRACTIONr_mcangle_it20.06631.8842202
X-RAY DIFFRACTIONr_mcangle_other20.06431.8912203
X-RAY DIFFRACTIONr_scbond_it17.21217.8241732
X-RAY DIFFRACTIONr_scbond_other17.20717.821733
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other22.48432.7232563
X-RAY DIFFRACTIONr_long_range_B_refined25.81158791
X-RAY DIFFRACTIONr_long_range_B_other25.81158791
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.9→2.975 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.442 68 -
Rwork0.368 1054 -
obs--85.52 %

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