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- PDB-8cu7: Crystal structure of A2AAR-StaR2-bRIL in complex with a novel A2a... -

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Basic information

Entry
Database: PDB / ID: 8cu7
TitleCrystal structure of A2AAR-StaR2-bRIL in complex with a novel A2a antagonist, LJ-4517
ComponentsAdenosine receptor A2a,Soluble cytochrome b562
KeywordsMEMBRANE PROTEIN / GPCR / A2a adenosine receptor / LCP / S277A mutant / 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 / positive regulation of urine volume ...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 / positive regulation of urine volume / NGF-independant TRKA activation / Surfactant metabolism / protein kinase C-activating G protein-coupled receptor signaling pathway / synaptic transmission, dopaminergic / synaptic transmission, cholinergic / inhibitory postsynaptic potential / negative regulation of vascular permeability / type 5 metabotropic glutamate receptor binding / positive regulation of glutamate secretion / blood circulation / intermediate filament / response to caffeine / eating behavior / presynaptic active zone / alpha-actinin binding / membrane depolarization / regulation of calcium ion transport / asymmetric synapse / axolemma / response to inorganic substance / cellular defense response / prepulse inhibition / phagocytosis / positive regulation of apoptotic signaling pathway / response to amphetamine / excitatory postsynaptic potential / presynaptic modulation of chemical synaptic transmission / positive regulation of synaptic transmission, glutamatergic / neuron projection morphogenesis / locomotory behavior / regulation of mitochondrial membrane potential / synaptic transmission, glutamatergic / central nervous system development / positive regulation of long-term synaptic potentiation / astrocyte activation / apoptotic signaling pathway / positive regulation of protein secretion / positive regulation of synaptic transmission, GABAergic / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating 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 / electron transfer activity / periplasmic space / calmodulin binding / response to xenobiotic stimulus / inflammatory response / iron ion binding / negative regulation of cell population proliferation / dendrite / neuronal cell body / glutamatergic synapse / lipid binding / apoptotic process / heme binding / protein-containing complex binding / regulation of DNA-templated transcription / enzyme binding / membrane / identical protein binding / 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 / TRIFLUOROETHANOL / 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: 2.05 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

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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)60,77041
Polymers49,6711
Non-polymers11,09940
Water3,189177
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area14630 Å2
ΔGint77 kcal/mol
Surface area21190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.456, 179.580, 140.873
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
DetailsThe authors 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: 49670.883 Da / Num. of mol.: 1 / Mutation: S277A
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 , 8 types, 217 molecules

#2: Chemical
ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C4H10O3
#3: 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
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Chemical
ChemComp-OLC / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / 1-Oleoyl-R-glycerol


Mass: 356.540 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C21H40O4
#6: Chemical...
ChemComp-OLA / OLEIC ACID / Oleic acid


Mass: 282.461 Da / Num. of mol.: 23 / Source method: obtained synthetically / Formula: C18H34O2
#7: Chemical ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H46O
#8: Chemical ChemComp-ETF / TRIFLUOROETHANOL / 2,2,2-Trifluoroethanol


Mass: 100.040 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3F3O
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 177 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: 2.51 Å3/Da / Density % sol: 51.03 %
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: Dec 6, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 2.05→44.9 Å / Num. obs: 28215 / % possible obs: 92.6 % / Redundancy: 6.5 % / Rmerge(I) obs: 0.15 / Net I/σ(I): 12.6
Reflection shellResolution: 2.05→2.11 Å / Redundancy: 1.6 % / Rmerge(I) obs: 0.417 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 1181 / % possible all: 64.4

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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: 2.05→44.89 Å / SU ML: 0.21 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 20.56 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2108 1445 5.12 %
Rwork0.1774 26770 -
obs0.1791 28215 87.27 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 142.89 Å2 / Biso mean: 38.2732 Å2 / Biso min: 9.62 Å2
Refinement stepCycle: final / Resolution: 2.05→44.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3057 0 626 177 3860
Biso mean--51.13 40.01 -
Num. residues----396
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.05-2.120.2975540.25521127118137
2.12-2.20.25231160.22232132224870
2.2-2.30.25091370.20462589272685
2.3-2.420.21611470.18322739288691
2.42-2.580.20271680.16792814298293
2.58-2.780.21371560.16642954311097
2.78-3.050.20481530.16873035318899
3.05-3.50.20471680.172530353203100
3.5-4.40.20891780.156731113289100
4.41-44.890.19641680.1893234340299
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)
10.44110.01210.00430.64480.38080.8872-0.0214-0.0907-0.0108-0.00220.0379-0.03840.0794-0.1609-0.05030.1079-0.0105-0.01240.13290.01990.0938-23.7803-5.020120.854
20.1937-0.061-0.10660.172-0.13690.18850.1805-0.2170.3488-0.3107-0.0735-0.13710.10180.05470.24610.35450.1078-0.07090.2097-0.03080.70080.0371-54.485519.9117
30.2287-0.02370.14510.4191-0.1750.6256-0.04860.0641-0.0602-0.26790.0919-0.11690.11630.0346-0.00730.1550.0004-0.00760.1458-0.00320.1218-18.1815-10.912210.7377
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid -3 through 208 )A-3 - 208
2X-RAY DIFFRACTION2chain 'A' and (resid 1001 through 1106 )A0
3X-RAY DIFFRACTION3chain 'A' and (resid 219 through 308 )A219 - 308

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