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- PDB-8c9w: Crystal structure of the adenosine A2A receptor (construct A2A-PS... -

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Basic information

Entry
Database: PDB / ID: 8c9w
TitleCrystal structure of the adenosine A2A receptor (construct A2A-PSB2-bRIL) complexed with Etrumadenant at the orthosteric pocket
ComponentsAdenosine receptor A2a,Soluble cytochrome b562
KeywordsMEMBRANE PROTEIN / GPCR / BRIL / antagonist / purinergic signaling / cancer immunotherapy
Function / homology
Function and homology information


regulation of norepinephrine secretion / positive regulation of circadian sleep/wake cycle, sleep / positive regulation of acetylcholine secretion, neurotransmission / negative regulation of alpha-beta T cell activation / Adenosine P1 receptors / G protein-coupled adenosine receptor activity / response to purine-containing compound / G protein-coupled adenosine receptor signaling pathway / NGF-independant TRKA activation / sensory perception ...regulation of norepinephrine secretion / positive regulation of circadian sleep/wake cycle, sleep / positive regulation of acetylcholine secretion, neurotransmission / negative regulation of alpha-beta T cell activation / Adenosine P1 receptors / G protein-coupled adenosine receptor activity / response to purine-containing compound / G protein-coupled adenosine receptor signaling pathway / NGF-independant TRKA activation / sensory perception / Surfactant metabolism / positive regulation of urine volume / synaptic transmission, dopaminergic / inhibitory postsynaptic potential / type 5 metabotropic glutamate receptor binding / negative regulation of vascular permeability / positive regulation of glutamate secretion / synaptic transmission, cholinergic / response to caffeine / blood circulation / intermediate filament / eating behavior / alpha-actinin binding / presynaptic active zone / regulation of calcium ion transport / membrane depolarization / asymmetric synapse / axolemma / phagocytosis / prepulse inhibition / cellular defense response / presynaptic modulation of chemical synaptic transmission / response to amphetamine / positive regulation of synaptic transmission, glutamatergic / neuron projection morphogenesis / regulation of mitochondrial membrane potential / central nervous system development / positive regulation of apoptotic signaling pathway / positive regulation of long-term synaptic potentiation / excitatory postsynaptic potential / positive regulation of synaptic transmission, GABAergic / synaptic transmission, glutamatergic / positive regulation of protein secretion / locomotory behavior / astrocyte activation / apoptotic signaling pathway / electron transport chain / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / negative regulation of inflammatory response / adenylate cyclase-activating G protein-coupled receptor signaling pathway / blood coagulation / vasodilation / cell-cell signaling / presynaptic membrane / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / negative regulation of neuron apoptotic process / postsynaptic membrane / periplasmic space / electron transfer activity / positive regulation of ERK1 and ERK2 cascade / calmodulin binding / inflammatory response / iron ion binding / response to xenobiotic stimulus / negative regulation of cell population proliferation / neuronal cell body / apoptotic process / lipid binding / heme binding / dendrite / regulation of DNA-templated transcription / protein-containing complex binding / glutamatergic synapse / 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 / OLEIC ACID / (2S)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / DI(HYDROXYETHYL)ETHER / Chem-U30 / Soluble cytochrome b562 / Adenosine receptor A2a
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.114 Å
AuthorsStrater, N. / Claff, T. / Schlegel, J.G. / Voss, J.H. / Vaassen, V. / Muller, C.E.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Commun Chem / Year: 2023
Title: Crystal structure of adenosine A 2A receptor in complex with clinical candidate Etrumadenant reveals unprecedented antagonist interaction.
Authors: Claff, T. / Schlegel, J.G. / Voss, J.H. / Vaassen, V.J. / Weisse, R.H. / Cheng, R.K.Y. / Markovic-Mueller, S. / Bucher, D. / Strater, N. / Muller, C.E.
History
DepositionJan 23, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 12, 2023Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Structure summary / Category: audit_author / chem_comp_atom / chem_comp_bond / Item: _audit_author.name
Revision 1.2Nov 6, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)52,33214
Polymers48,1571
Non-polymers4,17413
Water1,02757
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4310 Å2
ΔGint19 kcal/mol
Surface area20200 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.155, 178.226, 139.595
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221

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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: 48157.066 Da / Num. of mol.: 1
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 , 7 types, 70 molecules

#2: Chemical ChemComp-U30 / 3-[2-azanyl-6-[1-[[6-(2-oxidanylpropan-2-yl)pyridin-2-yl]methyl]-1,2,3-triazol-4-yl]pyrimidin-4-yl]-2-methyl-benzenecarbonitrile


Mass: 426.474 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22N8O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H46O
#4: Chemical
ChemComp-OLA / OLEIC ACID


Mass: 282.461 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C18H34O2
#5: Chemical ChemComp-OLC / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / 1-Oleoyl-R-glycerol


Mass: 356.540 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H40O4
#6: Chemical ChemComp-OLB / (2S)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate


Mass: 356.540 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H40O4
#7: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


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


Mass: 18.015 Da / Num. of mol.: 57 / 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: 2.53 Å3/Da / Density % sol: 51.36 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7.4
Details: 30 % (w/v) PEG400, 7 % (w/v) Tacsimate pH 7.0,100 mM HEPES-Na pH 7.4, 1.8 % (w/v) 2,5-hexandiol, 25 microM Etrumadenant

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P14 (MX2) / Wavelength: 0.97625 Å
DetectorType: DECTRIS EIGER2 S 16M / Detector: PIXEL / Date: Mar 4, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 2.114→38.243 Å / Num. obs: 21413 / % possible obs: 74.8 % / Redundancy: 13.3 % / CC1/2: 0.999 / Rmerge(I) obs: 0.13 / Rpim(I) all: 0.037 / Rrim(I) all: 0.136 / Net I/σ(I): 13.1
Reflection shellResolution: 2.114→2.316 Å / Rmerge(I) obs: 1.697 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 1072 / CC1/2: 0.529 / Rpim(I) all: 0.521 / Rrim(I) all: 1.78

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Processing

Software
NameVersionClassification
PHENIX1.20_4459refinement
XDSFeb 5, 2021 (BUILT 20210323)data reduction
STARANISO2.3.74data scaling
PHENIX1.20_4459phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.114→38.24 Å / SU ML: 0.27 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 31.15 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2665 994 4.64 %
Rwork0.1965 --
obs0.1997 21405 74.77 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.114→38.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3011 0 259 57 3327
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0123393
X-RAY DIFFRACTIONf_angle_d1.3054599
X-RAY DIFFRACTIONf_dihedral_angle_d14.5041317
X-RAY DIFFRACTIONf_chiral_restr0.052532
X-RAY DIFFRACTIONf_plane_restr0.008583
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.114-2.230.5429140.3298250X-RAY DIFFRACTION7
2.23-2.370.3361800.2521347X-RAY DIFFRACTION36
2.37-2.550.29521400.22593114X-RAY DIFFRACTION80
2.55-2.80.28291690.21383839X-RAY DIFFRACTION99
2.8-3.210.29321920.20463876X-RAY DIFFRACTION100
3.21-4.040.24091890.18473915X-RAY DIFFRACTION100
4.04-38.240.25542100.18664070X-RAY DIFFRACTION99

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