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- PDB-9h2x: Crystal structure of stabilized A2A adenosine receptor A2AR-StaR2... -

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Basic information

Entry
Database: PDB / ID: 9h2x
TitleCrystal structure of stabilized A2A adenosine receptor A2AR-StaR2-bRIL in complex with compound 7, a novel nanomolar A2A receptor antagonist from modern hit-finding with structure-guided de novo design
ComponentsAdenosine receptor A2a,Soluble cytochrome b562
KeywordsMEMBRANE PROTEIN / adenosine receptor / GPCR / antagonist / chemical hit
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 / Soluble cytochrome b562 / Adenosine receptor A2a
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsTian, G. / Maja, N.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
University of Cambridge United Kingdom
CitationJournal: To Be Published
Title: Identification of nanomolar adenosine A2A receptor ligands using reinforcement learning and structure-based drug design
Authors: Morgan, T. / Pierre, G.M. / Robert, J.G. / Maja, N. / Hannah, N. / Jonathan, S.M. / Jason, B. / Harwood, K. / Charlotte, F. / Nigel, A.S. / Tian, G. / Noel, M.O. / Francesca, D. / Andreas, B. / Chris, D.G.
History
DepositionOct 15, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 18, 2025Provider: repository / Type: Initial release

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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)55,41727
Polymers47,9971
Non-polymers7,42026
Water2,090116
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)39.349, 179.535, 140.115
Angle α, β, γ (deg.)90, 90, 90
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: 47996.746 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: Trichoplusia ni (cabbage looper) / References: UniProt: P29274, UniProt: P0ABE7

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Non-polymers , 5 types, 142 molecules

#2: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#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.: 21 / Source method: obtained synthetically / Formula: C18H34O2
#5: Chemical ChemComp-A1IR1 / 4-(furan-2-yl)-6-(6-imidazol-1-ylpyridin-2-yl)-1,3,5-triazin-2-amine


Mass: 305.294 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H11N7O / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 116 / 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: 2.58 Å3/Da / Density % sol: 52.29 %
Crystal growTemperature: 293 K / Method: lipidic cubic phase
Details: 0.l M tri-sodium citrate pH 5.3-5.4, 0.05 M sodium thiocyanate, 29-32% PEG400, 2% (v/v) 2,5-hexanediol and 0.5 mM theophylline.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.6199 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jan 25, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.6199 Å / Relative weight: 1
ReflectionResolution: 1.75→44.884 Å / Num. obs: 43855 / % possible obs: 90 % / Redundancy: 29.18 %
Details: Some remarks regarding the mmCIF items written, the PDB Exchange Dictionary (PDBx/mmCIF) Version 5.0 supporting the data files in the current PDB archive (dictionary version 5.325, last ...Details: Some remarks regarding the mmCIF items written, the PDB Exchange Dictionary (PDBx/mmCIF) Version 5.0 supporting the data files in the current PDB archive (dictionary version 5.325, last updated 2020-04-13: http://mmcif.wwpdb.org/dictionaries/mmcif_pdbx_v50.dic/Index/) and the actual quantities provided by MRFANA (https://github.com/githubgphl/MRFANA) from the autoPROC package (https://www.globalphasing.com/autoproc/). In general, the mmCIF categories here should provide items that are currently used in the PDB archive. If there are alternatives, the one recommended by the PDB developers has been selected. The distinction between *_all and *_obs quantities is not always clear: often only one version is actively used within the PDB archive (or is the one recommended by PDB developers). The intention of distinguishing between classes of reflections before and after some kind of observation criterion was applied, can in principle be useful - but such criteria change in various ways throughout the data processing steps (rejection of overloaded or too partial reflections, outlier/misfit rejections during scaling etc) and there is no retrospect computation of data scaling/merging statistics for the reflections used in the final refinement (where another observation criterion might have been applied). Typical data processing will usually only provide one version of statistics at various stages and these are given in the recommended item here, irrespective of the "_all" and "_obs" connotation, see e.g. the use of _reflns.pdbx_Rmerge_I_obs, _reflns.pdbx_Rrim_I_all and _reflns.pdbx_Rpim_I_all. Please note that all statistics related to "merged intensities" (or "merging") are based on inverse-variance weighting of the individual measurements making up a symmetry-unique reflection. This is standard for several decades now, even if some of the dictionary definitions seem to suggest that a simple "mean" or "average" intensity is being used instead. R-values are always given for all symmetry-equivalent reflections following Friedel's law, i.e. Bijvoet pairs are not treated separately (since we want to describe the overall mean intensity and not the mean I(+) and I(-) here). The Rrim metric is identical to the Rmeas R-value and only differs in name. _reflns.pdbx_number_measured_all is the number of measured intensities just before the final merging step (at which point no additional rejection takes place). _reflns.number_obs is the number of symmetry-unique observations, i.e. the result of merging those measurements via inverse-variance weighting. _reflns.pdbx_netI_over_sigmaI is based on the merged intensities (_reflns.number_obs) as expected. _reflns.pdbx_redundancy is synonymous with "multiplicity". The per-shell item _reflns_shell.number_measured_all corresponds to the overall value _reflns.pdbx_number_measured_all. The per-shell item _reflns_shell.number_unique_all corresponds to the overall value _reflns.number_obs. The per-shell item _reflns_shell.percent_possible_all corresponds to the overall value _reflns.percent_possible_obs. The per-shell item _reflns_shell.meanI_over_sigI_obs corresponds to the overall value given as _reflns.pdbx_netI_over_sigmaI. But be aware of the incorrect definition of the former in the current dictionary!
CC1/2: 0.994 / CC1/2 anomalous: -0.165 / Rmerge(I) obs: 0.4061 / Rpim(I) all: 0.0764 / Rrim(I) all: 0.4133 / AbsDiff over sigma anomalous: 0.756 / Aniso diffraction limit 1: 1.825 Å / Aniso diffraction limit 2: 1.756 Å / Aniso diffraction limit 3: 1.75 Å / Aniso diffraction limit axis 1 ortho1: 1 / Aniso diffraction limit axis 1 ortho2: 0 / Aniso diffraction limit axis 1 ortho3: 0 / Aniso diffraction limit axis 2 ortho1: 0 / Aniso diffraction limit axis 2 ortho2: 1 / Aniso diffraction limit axis 2 ortho3: 0 / Aniso diffraction limit axis 3 ortho1: 0 / Aniso diffraction limit axis 3 ortho2: 0 / Aniso diffraction limit axis 3 ortho3: 1 / Net I/σ(I): 11.13 / Num. measured all: 1279637 / Observed signal threshold: 1.2 / % possible anomalous: 90 / % possible ellipsoidal: 90 / % possible ellipsoidal anomalous: 90 / % possible spherical: 86.4 / % possible spherical anomalous: 86.1 / Redundancy anomalous: 15.32 / Signal type: local
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. measured obsNum. unique allNum. unique obsCC1/2CC1/2 anomalousRpim(I) allRrim(I) allAbsDiff over sigma anomalous% possible anomalous% possible ellipsoidal% possible ellipsoidal anomalous% possible spherical% possible spherical anomalousRedundancy anomalous% possible all
4.899-44.88427.440.078536.26841368413249324930.99-0.2670.01540.08010.60210099.910099.910015.6499.9
3.894-4.89927.540.099234.786528165281237023700.998-0.5070.01930.10110.68910010010010010014.87100
3.402-3.89427.690.162326.256515565155235323530.996-0.3160.03140.16530.75410010010010010014.77100
3.091-3.40228.80.266619.286700067000232623260.994-0.1220.05060.27140.78310010010010010015.29100
2.873-3.09129.610.373616.046765967659228522850.992-0.1270.06980.38010.75910010010010010015.62100
2.703-2.87329.960.484813.446884868848229822980.989-0.0350.09020.49320.76110010010010010015.76100
2.571-2.70330.330.57111.666794067940224022400.9850.0170.10540.58080.75310010010010010015.88100
2.462-2.57130.450.6969.516711267112220422040.98-0.0210.12830.70780.7610010010010010015.9100
2.369-2.46230.520.86187.96830068300223822380.9690.0140.15880.87650.76210010010010010015.97100
2.289-2.36930.670.99216.866766267662220622060.9520.0190.18221.00880.78110010010010010016.01100
2.22-2.28920.171.2084.64429444294219621960.897-0.0180.27021.23910.75610010010010010010.49100
2.158-2.2230.331.41194.986621366213218321830.908-0.0150.26111.4360.79310099.910099.910015.7999.9
2.101-2.15830.071.78643.946590665906219221920.867-0.0090.33111.81710.78510010010010010015.64100
2.052-2.10130.142.0833.466360063600211021100.8440.0230.38612.11880.7959897.99897.99815.6197.9
2.006-2.05230.52.50552.966474664746212321230.787-0.0150.4612.54790.7649797.19797.19715.7997.1
1.963-2.00630.53.06442.46425364253210721070.7540.0440.56353.11620.78895.995.895.995.895.915.895.8
1.922-1.96330.343.80511.946372163721210021000.6690.0120.70233.86990.7658887.78887.78815.7287.7
1.881-1.92229.384.24381.755911959119201220120.628-0.0230.79694.31870.76781.580.481.580.481.515.1180.4
1.837-1.88127.734.84451.535368053680193619360.5430.0050.93564.9350.75665.764.665.764.665.714.264.6
1.75-1.83732.255.79181.416073560735188318830.540.0131.03755.88470.72638.938.538.927.827.916.6438.5

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
autoPROCdata processing
autoPROC2.3.87data processing
autoPROCdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.75→25.2 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.932 / SU R Cruickshank DPI: 0.132 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.131 / SU Rfree Blow DPI: 0.117 / SU Rfree Cruickshank DPI: 0.118
RfactorNum. reflection% reflectionSelection details
Rfree0.226 2200 -RANDOM
Rwork0.2061 ---
obs0.2071 43834 86.3 %-
Displacement parametersBiso mean: 31.79 Å2
Baniso -1Baniso -2Baniso -3
1-0.5228 Å20 Å20 Å2
2--4.0558 Å20 Å2
3----4.5786 Å2
Refine analyzeLuzzati coordinate error obs: 0.25 Å
Refinement stepCycle: LAST / Resolution: 1.75→25.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2968 0 386 116 3470
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0083543HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.84767HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1344SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes559HARMONIC5
X-RAY DIFFRACTIONt_it3543HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion445SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact3098SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.02
X-RAY DIFFRACTIONt_other_torsion15.63
LS refinement shellResolution: 1.75→1.8 Å
RfactorNum. reflection% reflection
Rfree0.3159 51 -
Rwork0.2594 --
obs0.2625 877 19.62 %
Refinement TLS params.

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)
10.1654-0.07650.08030.7983-0.00930.06080.0071-0.08310.0299-0.0831-0.0016-0.04360.0299-0.0436-0.00550.0235-0.00880.00070.01890.0097-0.0564-16.7472-17.967618.2843
20.253-0.07430.0970.4602-0.01070.1301-0.0178-0.05580.0218-0.05580.0003-0.03770.0218-0.03770.0175-0.01710.01090.00890.03420.0015-0.056-21.4419-1.241118.2154
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|0 - 305}A0 - 305
2X-RAY DIFFRACTION2{ A|1201 - 1226}A1201 - 1226

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