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- PDB-6li2: Crystal structure of GPR52 ligand free form with rubredoxin fusion -

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Basic information

Entry
Database: PDB / ID: 6li2
TitleCrystal structure of GPR52 ligand free form with rubredoxin fusion
ComponentsChimera of G-protein coupled receptor 52 and Rubredoxin
KeywordsMEMBRANE PROTEIN / Human GPR52 receptor / Class A / orphan GPCR / apo form / rubredoxin / LCP
Function / homology
Function and homology information


alkane catabolic process / G protein-coupled photoreceptor activity / cellular response to light stimulus / phototransduction / locomotory behavior / G protein-coupled receptor activity / electron transfer activity / response to xenobiotic stimulus / iron ion binding / G protein-coupled receptor signaling pathway / plasma membrane
Similarity search - Function
Rubredoxin / Rubredoxin, iron-binding site / Rubredoxin signature. / Rubredoxin domain / Rubredoxin / Rubredoxin-like domain / Rubredoxin-like domain profile. / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM ...Rubredoxin / Rubredoxin, iron-binding site / Rubredoxin signature. / Rubredoxin domain / Rubredoxin / Rubredoxin-like domain / Rubredoxin-like domain profile. / 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
(2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / DI(HYDROXYETHYL)ETHER / Rubredoxin / G-protein coupled receptor 52
Similarity search - Component
Biological speciesHomo sapiens (human)
Clostridium pasteurianum (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsLuo, Z.P. / Lin, X. / Xu, F. / Han, G.W.
Funding support China, 1items
OrganizationGrant numberCountry
National Science Foundation (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 Rubredoxin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,60414
Polymers42,5101
Non-polymers4,09313
Water32418
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area110 Å2
ΔGint-0 kcal/mol
Surface area19130 Å2
MethodPISA
Unit cell
Length a, b, c (Å)77.223, 113.229, 138.615
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
DetailsAUTHORS STATE THAT THE BIOLOGICAL UNIT IS UNKNOWN.

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Components

#1: Protein Chimera of G-protein coupled receptor 52 and Rubredoxin / Rd


Mass: 42510.426 Da / Num. of mol.: 1 / Mutation: W278Q, C314P, S318A, N321D, V323T
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Clostridium pasteurianum (bacteria)
Gene: GPR52 / Cell line (production host): f9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9Y2T5, UniProt: P00268
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#3: Chemical
ChemComp-OLC / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / 1-Oleoyl-R-glycerol


Mass: 356.540 Da / Num. of mol.: 11 / Source method: obtained synthetically / Formula: C21H40O4
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 18 / Source method: isolated from a natural source / Formula: H2O
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: 3.83 Å3/Da / Density % sol: 67.9 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase
Details: 0.08-0.1 M magnesium sulphate, 0.1 M sodium cacodylate trihydrate pH 6.2, and 28-31% PEG300

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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: 2.8→50 Å / Num. obs: 15032 / % possible obs: 96.9 % / Redundancy: 8.2 % / Biso Wilson estimate: 47.78 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.164 / Rpim(I) all: 0.054 / Net I/σ(I): 13.2
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 8 % / Rmerge(I) obs: 0.967 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 1457 / CC1/2: 0.895 / Rpim(I) all: 0.328 / % possible all: 96.1

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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: 2.8→29.25 Å / Cor.coef. Fo:Fc: 0.889 / Cor.coef. Fo:Fc free: 0.892 / SU B: 32.117 / SU ML: 0.315 / Cross valid method: THROUGHOUT / ESU R: 16.343 / ESU R Free: 0.401 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS Authors aniso-corrected the observed data by STARANISO which remove weak reflections.
RfactorNum. reflection% reflectionSelection details
Rfree0.26295 612 4.9 %RANDOM
Rwork0.24112 ---
obs0.24217 11830 81.1 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 61.372 Å2
Baniso -1Baniso -2Baniso -3
1-2.26 Å20 Å20 Å2
2---3.97 Å20 Å2
3---1.71 Å2
Refinement stepCycle: 1 / Resolution: 2.8→29.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2761 0 177 18 2956
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0133015
X-RAY DIFFRACTIONr_bond_other_d0.0070.0172798
X-RAY DIFFRACTIONr_angle_refined_deg1.441.6894069
X-RAY DIFFRACTIONr_angle_other_deg0.8051.6666475
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.4945345
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.23721.545123
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.09915433
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.9481510
X-RAY DIFFRACTIONr_chiral_restr0.0730.2393
X-RAY DIFFRACTIONr_gen_planes_refined0.0420.023178
X-RAY DIFFRACTIONr_gen_planes_other0.0360.02660
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_it8.5629.931386
X-RAY DIFFRACTIONr_mcbond_other8.5379.9331385
X-RAY DIFFRACTIONr_mcangle_it11.81818.6231729
X-RAY DIFFRACTIONr_mcangle_other11.82718.6251730
X-RAY DIFFRACTIONr_scbond_it9.05211.4561629
X-RAY DIFFRACTIONr_scbond_other9.04911.4551630
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other12.48420.7572341
X-RAY DIFFRACTIONr_long_range_B_refined18.21849693
X-RAY DIFFRACTIONr_long_range_B_other18.21849688
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.8→2.873 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.272 26 -
Rwork0.258 566 -
obs--53 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.4022-0.2062-0.11890.42060.40291.0024-0.0350.00630.0030.0847-0.02730.00190.1184-0.14440.06230.0684-0.03780.00110.3205-0.00560.00625.710420.651937.6473
21.3930.3127-1.13220.25240.17533.97390.0520.0569-0.0037-0.0188-0.0510.0491-0.02810.0843-0.0010.0563-0.0306-0.02660.32970.01710.030623.035234.556269.9635
31.09060.38881.05340.17860.37032.0785-0.0525-0.0652-0.0372-0.0156-0.0662-0.06160.2166-0.25290.11870.0812-0.00790.03270.32310.02630.079616.693426.217441.3018
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A23 - 235
2X-RAY DIFFRACTION2A1001 - 1054
3X-RAY DIFFRACTION3A263 - 605

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