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- PDB-7yu4: Human Lysophosphatidic Acid Receptor 1-Gi complex bound to ONO-07... -

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Basic information

Entry
Database: PDB / ID: 7yu4
TitleHuman Lysophosphatidic Acid Receptor 1-Gi complex bound to ONO-0740556, focused on receptor
ComponentsLysophosphatidic acid receptor 1
KeywordsMEMBRANE PROTEIN / GPCR
Function / homology
Function and homology information


cellular response to 1-oleoyl-sn-glycerol 3-phosphate / lysophosphatidic acid receptor activity / positive regulation of smooth muscle cell chemotaxis / calmodulin dependent kinase signaling pathway / Lysosphingolipid and LPA receptors / lysophosphatidic acid binding / negative regulation of cilium assembly / regulation of synaptic vesicle cycle / cellular response to oxygen levels / oligodendrocyte development ...cellular response to 1-oleoyl-sn-glycerol 3-phosphate / lysophosphatidic acid receptor activity / positive regulation of smooth muscle cell chemotaxis / calmodulin dependent kinase signaling pathway / Lysosphingolipid and LPA receptors / lysophosphatidic acid binding / negative regulation of cilium assembly / regulation of synaptic vesicle cycle / cellular response to oxygen levels / oligodendrocyte development / corpus callosum development / bleb assembly / regulation of metabolic process / optic nerve development / negative regulation of cAMP-mediated signaling / regulation of postsynaptic neurotransmitter receptor internalization / positive regulation of dendritic spine development / positive regulation of Rho protein signal transduction / activation of phospholipase C activity / GABA-ergic synapse / G-protein alpha-subunit binding / positive regulation of stress fiber assembly / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / myelination / cerebellum development / neurogenesis / cell chemotaxis / dendritic shaft / PDZ domain binding / G protein-coupled receptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / negative regulation of neuron projection development / presynaptic membrane / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / regulation of cell shape / G alpha (i) signalling events / postsynaptic membrane / G alpha (q) signalling events / positive regulation of canonical NF-kappaB signal transduction / dendritic spine / positive regulation of MAPK cascade / endosome / positive regulation of apoptotic process / G protein-coupled receptor signaling pathway / neuronal cell body / glutamatergic synapse / cell surface / plasma membrane / cytoplasm
Similarity search - Function
Lysophosphatidic acid receptor EDG-2 / Lysophosphatidic acid receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / 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
Chem-K6L / Lysophosphatidic acid receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsAkasaka, H. / Shihoya, W. / Nureki, O.
Funding support Japan, 1items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)21H05037 Japan
CitationJournal: Nat Commun / Year: 2022
Title: Structure of the active G-coupled human lysophosphatidic acid receptor 1 complexed with a potent agonist.
Authors: Hiroaki Akasaka / Tatsuki Tanaka / Fumiya K Sano / Yuma Matsuzaki / Wataru Shihoya / Osamu Nureki /
Abstract: Lysophosphatidic acid receptor 1 (LPA) is one of the six G protein-coupled receptors activated by the bioactive lipid, lysophosphatidic acid (LPA). LPA is a drug target for various diseases, ...Lysophosphatidic acid receptor 1 (LPA) is one of the six G protein-coupled receptors activated by the bioactive lipid, lysophosphatidic acid (LPA). LPA is a drug target for various diseases, including cancer, inflammation, and neuropathic pain. Notably, LPA agonists have potential therapeutic value for obesity and urinary incontinence. Here, we report a cryo-electron microscopy structure of the active human LPA-G complex bound to ONO-0740556, an LPA analog with more potent activity against LPA. Our structure elucidated the details of the agonist binding mode and receptor activation mechanism mediated by rearrangements of transmembrane segment 7 and the central hydrophobic core. A structural comparison of LPA and other phylogenetically-related lipid-sensing GPCRs identified the structural determinants for lipid preference of LPA. Moreover, we characterized the structural polymorphisms at the receptor-G-protein interface, which potentially reflect the G-protein dissociation process. Our study provides insights into the detailed mechanism of LPA binding to agonists and paves the way toward the design of drug-like agonists targeting LPA.
History
DepositionAug 16, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 5, 2022Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Lysophosphatidic acid receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,3512
Polymers42,9361
Non-polymers4151
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Lysophosphatidic acid receptor 1 / / LPA receptor 1 / LPA-1 / Lysophosphatidic acid receptor Edg-2


Mass: 42936.004 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LPAR1, EDG2, LPA1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q92633
#2: Chemical ChemComp-K6L / [(2~{R})-2-[5-(2-hexylphenyl)pentanoylamino]-3-oxidanyl-propyl] dihydrogen phosphate


Mass: 415.461 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H34NO6P / 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 Lysophosphatidic Acid Receptor 1 bound to ONO-0740556
Type: COMPLEX / Entity ID: #1 / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 8
SpecimenConc.: 7 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

SoftwareName: REFMAC / Version: 5.8.0267 / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 181071 / Symmetry type: POINT
RefinementResolution: 3.3→88.44 Å / Cor.coef. Fo:Fc: 0.803 / SU B: 32.341 / SU ML: 0.472 / ESU R: 0.592
Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflection
Rwork0.47393 --
obs0.47393 24712 100 %
Solvent computationSolvent model: PARAMETERS FOR MASK CACLULATION
Displacement parametersBiso mean: 99.316 Å2
Refinement stepCycle: 1 / Total: 2251
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
ELECTRON MICROSCOPYr_bond_refined_d0.0080.0132308
ELECTRON MICROSCOPYr_bond_other_d0.0010.0172180
ELECTRON MICROSCOPYr_angle_refined_deg1.2231.6213153
ELECTRON MICROSCOPYr_angle_other_deg1.6351.5574948
ELECTRON MICROSCOPYr_dihedral_angle_1_deg5.315288
ELECTRON MICROSCOPYr_dihedral_angle_2_deg35.78720.95794
ELECTRON MICROSCOPYr_dihedral_angle_3_deg15.16415339
ELECTRON MICROSCOPYr_dihedral_angle_4_deg9.7951510
ELECTRON MICROSCOPYr_chiral_restr0.0740.2318
ELECTRON MICROSCOPYr_gen_planes_refined0.0060.022573
ELECTRON MICROSCOPYr_gen_planes_other0.0030.02569
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_it9.83310.2931158
ELECTRON MICROSCOPYr_mcbond_other9.81510.2941157
ELECTRON MICROSCOPYr_mcangle_it16.83215.4041444
ELECTRON MICROSCOPYr_mcangle_other16.83115.4051445
ELECTRON MICROSCOPYr_scbond_it9.95211.6711150
ELECTRON MICROSCOPYr_scbond_other9.95411.6641147
ELECTRON MICROSCOPYr_scangle_it
ELECTRON MICROSCOPYr_scangle_other17.19416.9331710
ELECTRON MICROSCOPYr_long_range_B_refined33.8419527
ELECTRON MICROSCOPYr_long_range_B_other33.8399528
ELECTRON MICROSCOPYr_rigid_bond_restr
ELECTRON MICROSCOPYr_sphericity_free
ELECTRON MICROSCOPYr_sphericity_bonded
LS refinement shellResolution: 3.301→3.387 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0 0 -
Rwork1.384 1782 -
obs--100 %

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