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- PDB-8xbg: Human GPR34 -Gi complex bound to S3E-LysoPS, receptor focused -

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Basic information

Entry
Database: PDB / ID: 8xbg
TitleHuman GPR34 -Gi complex bound to S3E-LysoPS, receptor focused
ComponentsProbable G-protein coupled receptor 34
KeywordsMEMBRANE PROTEIN / GPCR
Function / homology
Function and homology information


G protein-coupled purinergic nucleotide receptor activity / G protein-coupled receptor activity / G protein-coupled receptor signaling pathway / plasma membrane
Similarity search - Function
: / 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
: / Probable G-protein coupled receptor 34
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.43 Å
AuthorsKawahara, R. / Shihoya, W. / Nureki, O.
Funding support Japan, 1items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)21H05037 Japan
CitationJournal: Nat Commun / Year: 2024
Title: Structural basis for lysophosphatidylserine recognition by GPR34.
Authors: Tamaki Izume / Ryo Kawahara / Akiharu Uwamizu / Luying Chen / Shun Yaginuma / Jumpei Omi / Hiroki Kawana / Fengjue Hou / Fumiya K Sano / Tatsuki Tanaka / Kazuhiro Kobayashi / Hiroyuki H ...Authors: Tamaki Izume / Ryo Kawahara / Akiharu Uwamizu / Luying Chen / Shun Yaginuma / Jumpei Omi / Hiroki Kawana / Fengjue Hou / Fumiya K Sano / Tatsuki Tanaka / Kazuhiro Kobayashi / Hiroyuki H Okamoto / Yoshiaki Kise / Tomohiko Ohwada / Junken Aoki / Wataru Shihoya / Osamu Nureki /
Abstract: GPR34 is a recently identified G-protein coupled receptor, which has an immunomodulatory role and recognizes lysophosphatidylserine (LysoPS) as a putative ligand. Here, we report cryo-electron ...GPR34 is a recently identified G-protein coupled receptor, which has an immunomodulatory role and recognizes lysophosphatidylserine (LysoPS) as a putative ligand. Here, we report cryo-electron microscopy structures of human GPR34-G complex bound with one of two ligands bound: either the LysoPS analogue S3E-LysoPS, or M1, a derivative of S3E-LysoPS in which oleic acid is substituted with a metabolically stable aromatic fatty acid surrogate. The ligand-binding pocket is laterally open toward the membrane, allowing lateral entry of lipidic agonists into the cavity. The amine and carboxylate groups of the serine moiety are recognized by the charged residue cluster. The acyl chain of S3E-LysoPS is bent and fits into the L-shaped hydrophobic pocket in TM4-5 gap, and the aromatic fatty acid surrogate of M1 fits more appropriately. Molecular dynamics simulations further account for the LysoPS-regioselectivity of GPR34. Thus, using a series of structural and physiological experiments, we provide evidence that chemically unstable 2-acyl LysoPS is the physiological ligand for GPR34. Overall, we anticipate the present structures will pave the way for development of novel anticancer drugs that specifically target GPR34.
History
DepositionDec 6, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 15, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Probable G-protein coupled receptor 34
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,2542
Polymers45,7031
Non-polymers5521
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Probable G-protein coupled receptor 34


Mass: 45702.742 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GPR34 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9UPC5
#2: Chemical ChemComp-KW0 / (2~{S})-2-azanyl-3-[[(2~{R})-1-ethoxy-3-[(~{Z})-octadec-9-enoyl]oxy-propan-2-yl]oxy-oxidanyl-phosphoryl]oxy-propanoic acid


Mass: 551.650 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H50NO9P / 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: Human GPR34-Gi complex bound to S3E-LysoPS, receptor focused
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 8
SpecimenConc.: 12 mg/ml / Embedding 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: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.43 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 79925 / Symmetry type: POINT
RefinementResolution: 3.43→3.43 Å / Cor.coef. Fo:Fc: 0.809 / SU B: 16.774 / SU ML: 0.274 / ESU R: 0.261
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.48181 --
obs0.48181 85224 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 142.074 Å2
Refinement stepCycle: 1 / Total: 2603
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0140.0132659
ELECTRON MICROSCOPYr_bond_other_d00.0172704
ELECTRON MICROSCOPYr_angle_refined_deg1.5481.6253586
ELECTRON MICROSCOPYr_angle_other_deg1.6541.5686187
ELECTRON MICROSCOPYr_dihedral_angle_1_deg4.5815315
ELECTRON MICROSCOPYr_dihedral_angle_2_deg28.4120.811111
ELECTRON MICROSCOPYr_dihedral_angle_3_deg14.915493
ELECTRON MICROSCOPYr_dihedral_angle_4_deg16.6141513
ELECTRON MICROSCOPYr_chiral_restr0.0960.2366
ELECTRON MICROSCOPYr_gen_planes_refined0.0090.022841
ELECTRON MICROSCOPYr_gen_planes_other0.0030.02637
ELECTRON MICROSCOPYr_nbd_refined
ELECTRON MICROSCOPYr_nbd_other
ELECTRON MICROSCOPYr_nbtor_refined
ELECTRON MICROSCOPYr_nbtor_other
ELECTRON MICROSCOPYr_xyhbond_nbd_refined
ELECTRON MICROSCOPYr_xyhbond_nbd_other
ELECTRON MICROSCOPYr_metal_ion_refined
ELECTRON MICROSCOPYr_metal_ion_other
ELECTRON MICROSCOPYr_symmetry_vdw_refined
ELECTRON MICROSCOPYr_symmetry_vdw_other
ELECTRON MICROSCOPYr_symmetry_hbond_refined
ELECTRON MICROSCOPYr_symmetry_hbond_other
ELECTRON MICROSCOPYr_symmetry_metal_ion_refined
ELECTRON MICROSCOPYr_symmetry_metal_ion_other
ELECTRON MICROSCOPYr_mcbond_it28.06613.2781266
ELECTRON MICROSCOPYr_mcbond_other28.06913.2811265
ELECTRON MICROSCOPYr_mcangle_it40.17719.8611579
ELECTRON MICROSCOPYr_mcangle_other40.16619.861580
ELECTRON MICROSCOPYr_scbond_it27.89216.0261393
ELECTRON MICROSCOPYr_scbond_other27.88216.0281394
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other42.46122.9252008
ELECTRON MICROSCOPYr_long_range_B_refined56.46410991
ELECTRON MICROSCOPYr_long_range_B_other56.46110992
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 2.9→2.975 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork0.746 6259 -
obs--100 %

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