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- PDB-8cu6: Crystal structure of A2AAR-StaR2-S277-bRIL in complex with a nove... -

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Basic information

Entry
Database: PDB / ID: 8cu6
TitleCrystal structure of A2AAR-StaR2-S277-bRIL in complex with a novel A2a antagonist, LJ-4517
ComponentsAdenosine receptor A2a,Soluble cytochrome b562
KeywordsMEMBRANE PROTEIN / GPCR / A2a adenosine receptor / LCP / nucleoside / antagonist / molecular dynamics
Function / homology
Function and homology information


positive regulation of acetylcholine secretion, neurotransmission / positive regulation of circadian sleep/wake cycle, sleep / regulation of norepinephrine secretion / negative regulation of alpha-beta T cell activation / Adenosine P1 receptors / G protein-coupled adenosine receptor activity / G protein-coupled adenosine receptor signaling pathway / response to purine-containing compound / sensory perception / NGF-independant TRKA activation ...positive regulation of acetylcholine secretion, neurotransmission / positive regulation of circadian sleep/wake cycle, sleep / regulation of norepinephrine secretion / negative regulation of alpha-beta T cell activation / Adenosine P1 receptors / G protein-coupled adenosine receptor activity / G protein-coupled adenosine receptor signaling pathway / response to purine-containing compound / sensory perception / NGF-independant TRKA activation / Surfactant metabolism / positive regulation of urine volume / synaptic transmission, dopaminergic / inhibitory postsynaptic potential / negative regulation of vascular permeability / : / type 5 metabotropic glutamate receptor binding / synaptic transmission, cholinergic / positive regulation of glutamate secretion / blood circulation / response to caffeine / intermediate filament / eating behavior / alpha-actinin binding / presynaptic active zone / regulation of calcium ion transport / membrane depolarization / asymmetric synapse / axolemma / cellular defense response / prepulse inhibition / phagocytosis / presynaptic modulation of chemical synaptic transmission / response to amphetamine / positive regulation of synaptic transmission, glutamatergic / neuron projection morphogenesis / excitatory postsynaptic potential / regulation of mitochondrial membrane potential / positive regulation of long-term synaptic potentiation / apoptotic signaling pathway / central nervous system development / synaptic transmission, glutamatergic / positive regulation of synaptic transmission, GABAergic / locomotory behavior / positive regulation of protein secretion / astrocyte activation / positive regulation of apoptotic signaling pathway / electron transport chain / adenylate cyclase-activating G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / negative regulation of inflammatory response / vasodilation / blood coagulation / cell-cell signaling / presynaptic membrane / G alpha (s) signalling events / postsynaptic membrane / negative regulation of neuron apoptotic process / periplasmic space / electron transfer activity / calmodulin binding / inflammatory response / iron ion binding / response to xenobiotic stimulus / negative regulation of cell population proliferation / neuronal cell body / lipid binding / glutamatergic synapse / heme binding / dendrite / regulation of DNA-templated transcription / protein-containing complex binding / apoptotic process / enzyme binding / identical protein binding / membrane / plasma membrane
Similarity search - Function
Adenosine A2A receptor / Adenosine receptor / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / 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
CHOLESTEROL / Chem-LJX / OLEIC ACID / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / DI(HYDROXYETHYL)ETHER / Soluble cytochrome b562 / Adenosine receptor A2a
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsShiriaeva, A. / Park, D.-J. / Kim, G. / Lee, Y. / Hou, X. / Jarhad, D.B. / Kim, G. / Yu, J. / Hyun, Y.E. / Kim, W. ...Shiriaeva, A. / Park, D.-J. / Kim, G. / Lee, Y. / Hou, X. / Jarhad, D.B. / Kim, G. / Yu, J. / Hyun, Y.E. / Kim, W. / Gao, Z.-G. / Jacobson, K.A. / Han, G.W. / Stevens, R.C. / Jeong, L.S. / Choi, S. / Cherezov, V.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)DK31117 United States
CitationJournal: J.Med.Chem. / Year: 2022
Title: GPCR Agonist-to-Antagonist Conversion: Enabling the Design of Nucleoside Functional Switches for the A 2A Adenosine Receptor.
Authors: Shiriaeva, A. / Park, D. / Kim, G. / Lee, Y. / Hou, X. / Jarhad, D.B. / Kim, G. / Yu, J. / Hyun, Y.E. / Kim, W. / Gao, Z.G. / Jacobson, K.A. / Han, G.W. / Stevens, R.C. / Jeong, L.S. / Choi, S. / Cherezov, V.
History
DepositionMay 16, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 31, 2022Provider: repository / Type: Initial release
Revision 1.1Sep 21, 2022Group: 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
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Adenosine receptor A2a,Soluble cytochrome b562
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,94125
Polymers49,6871
Non-polymers7,25524
Water72140
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9400 Å2
ΔGint56 kcal/mol
Surface area20320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.229, 179.055, 140.010
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
DetailsAuthors state that the biological unit is unknown.

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Adenosine receptor A2a,Soluble cytochrome b562 / Cytochrome b-562


Mass: 49686.883 Da / Num. of mol.: 1 / Mutation: yes
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (E. coli)
Gene: ADORA2A, ADORA2, cybC / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P29274, UniProt: P0ABE7

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Non-polymers , 6 types, 64 molecules

#2: Chemical
ChemComp-OLA / OLEIC ACID


Mass: 282.461 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: C18H34O2
#3: Chemical ChemComp-OLC / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / 1-Oleoyl-R-glycerol


Mass: 356.540 Da / Num. of mol.: 3 / 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: Chemical ChemComp-LJX / (2R,3R,4R)-2-[(8P)-6-amino-2-(hex-1-yn-1-yl)-8-(thiophen-2-yl)-9H-purin-9-yl]oxolane-3,4-diol


Mass: 399.467 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H21N5O3S / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H46O
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 40 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.47 Å3/Da / Density % sol: 50.29 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase
Details: 0.1 M HEPES, pH 5.3, 0.05 M sodium thiocyanate, 30% PEG400, 2% 2,2,2-trifluoroethanol

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Data collection

DiffractionMean temperature: 123 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.033 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 30, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 2.8→42.64 Å / Num. obs: 10844 / % possible obs: 85.5 % / Redundancy: 4.3 % / Rmerge(I) obs: 0.211 / Net I/σ(I): 5.7
Reflection shellResolution: 2.8→2.85 Å / Rmerge(I) obs: 0.549 / Mean I/σ(I) obs: 1 / Num. unique obs: 402

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PDB_EXTRACT3.27data extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4EIY

4eiy


Resolution: 2.8→36.96 Å / SU ML: 0.41 / Cross valid method: THROUGHOUT / σ(F): 1.39 / Phase error: 23.76 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2472 552 5.13 %
Rwork0.196 10203 -
obs0.1987 10755 84.82 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 109.48 Å2 / Biso mean: 47.1932 Å2 / Biso min: 19.53 Å2
Refinement stepCycle: final / Resolution: 2.8→36.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3009 0 421 40 3470
Biso mean--43.71 36.47 -
Num. residues----393
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 4

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.8-3.080.32061280.25172354248281
3.08-3.520.32081350.21992620275588
3.52-4.440.22271500.172583273387
4.44-36.960.21031390.18792646278584

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