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- PDB-8cic: Crystal structure of stabilized A2A adenosine receptor A2AR-StaR2... -

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Basic information

Entry
Database: PDB / ID: 8cic
TitleCrystal structure of stabilized A2A adenosine receptor A2AR-StaR2-bRIL in complex with clinical candidate Etrumadenant
ComponentsAdenosine receptor A2a,Soluble cytochrome b562
KeywordsSIGNALING PROTEIN / G-protein coupled receptor
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 / synaptic transmission, dopaminergic / : / inhibitory postsynaptic potential / negative regulation of vascular permeability / synaptic transmission, cholinergic / type 5 metabotropic glutamate receptor binding / positive regulation of glutamate secretion / blood circulation / response to caffeine / intermediate filament / eating behavior / presynaptic active zone / alpha-actinin binding / membrane depolarization / regulation of calcium ion transport / asymmetric synapse / axolemma / : / cellular defense response / prepulse inhibition / phagocytosis / response to amphetamine / presynaptic modulation of chemical synaptic transmission / excitatory postsynaptic potential / positive regulation of synaptic transmission, glutamatergic / neuron projection morphogenesis / regulation of mitochondrial membrane potential / synaptic transmission, glutamatergic / positive regulation of long-term synaptic potentiation / locomotory behavior / central nervous system development / astrocyte activation / positive regulation of synaptic transmission, GABAergic / positive regulation of protein secretion / apoptotic signaling pathway / electron transport chain / positive regulation of apoptotic signaling pathway / 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 / periplasmic space / electron transfer activity / calmodulin binding / response to xenobiotic stimulus / inflammatory response / iron ion binding / negative regulation of cell population proliferation / neuronal cell body / glutamatergic synapse / lipid binding / apoptotic process / dendrite / heme binding / protein-containing complex binding / regulation of DNA-templated transcription / 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 / Chem-U30 / Soluble cytochrome b562 / Adenosine receptor A2a
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.102 Å
AuthorsCheng, R.K.Y. / Markovic-Mueller, S. / Hennig, M.
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
DepositionFeb 9, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 31, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 14, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name

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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)57,09830
Polymers48,0131
Non-polymers9,08529
Water2,270126
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area9040 Å2
ΔGint21 kcal/mol
Surface area20930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.360, 179.091, 140.573
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: 48012.746 Da / Num. of mol.: 1 / Mutation: A54L,T88A,K122A,V239A,R107A,L202A,L235A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADORA2A, ADORA2, cybC / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P29274, UniProt: P0ABE7

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Non-polymers , 7 types, 155 molecules

#2: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: Na
#3: 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
#4: Chemical
ChemComp-CLR / CHOLESTEROL


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


Mass: 282.461 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: C18H34O2
#6: Chemical ChemComp-OLB / (2S)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate


Mass: 356.540 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C21H40O4
#7: Chemical
ChemComp-OLC / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / 1-Oleoyl-R-glycerol


Mass: 356.540 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C21H40O4
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 126 / 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: 2.58 Å3/Da / Density % sol: 52.32 %
Crystal growTemperature: 294 K / Method: lipidic cubic phase / pH: 5
Details: 0.1 M sodium citrate pH 5.0, 50 mM sodium thiocyanate, 3 % (v/v) 2-methyl-2,4-pentanediol (MPD), 21-32 % (w/v) PEG400, and 2 mM theophylline

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.99997 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Nov 29, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99997 Å / Relative weight: 1
ReflectionResolution: 2.1→46.86 Å / Num. obs: 55857 / % possible obs: 100 % / Redundancy: 13.2 % / CC1/2: 0.999 / Rmerge(I) obs: 0.172 / Rpim(I) all: 0.049 / Rrim(I) all: 0.179 / Χ2: 0.97 / Net I/σ(I): 11.1
Reflection shellResolution: 2.1→2.16 Å / % possible obs: 99.6 % / Redundancy: 13.4 % / Rmerge(I) obs: 2.177 / Num. measured all: 31527 / Num. unique obs: 2361 / CC1/2: 0.499 / Rpim(I) all: 0.613 / Rrim(I) all: 2.263 / Χ2: 0.95 / Net I/σ(I) obs: 1.2

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Processing

Software
NameVersionClassification
PHENIX1.14refinement
Aimless0.7.3data scaling
XDSbuilt 20161205data reduction
PHASER2.8.2phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.102→44.773 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 0.28 / Phase error: 23.09 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2144 2840 5.08 %
Rwork0.1904 --
obs0.1916 55857 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.102→44.773 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2982 0 509 126 3617
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0033631
X-RAY DIFFRACTIONf_angle_d0.5494860
X-RAY DIFFRACTIONf_dihedral_angle_d15.8011988
X-RAY DIFFRACTIONf_chiral_restr0.036545
X-RAY DIFFRACTIONf_plane_restr0.003574
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.102-2.13780.37661090.30852622X-RAY DIFFRACTION99
2.1378-2.17670.34011520.29712693X-RAY DIFFRACTION100
2.1767-2.21860.30761360.2722613X-RAY DIFFRACTION100
2.2186-2.26380.32131490.25692642X-RAY DIFFRACTION100
2.2638-2.31310.29071460.25232680X-RAY DIFFRACTION100
2.3131-2.36690.26631380.24632615X-RAY DIFFRACTION100
2.3669-2.42610.25731710.23452662X-RAY DIFFRACTION100
2.4261-2.49160.29571510.2342635X-RAY DIFFRACTION100
2.4916-2.5650.25141520.21422618X-RAY DIFFRACTION100
2.565-2.64770.21641280.19512699X-RAY DIFFRACTION100
2.6477-2.74240.23271270.19472629X-RAY DIFFRACTION100
2.7424-2.85210.1891280.18362693X-RAY DIFFRACTION100
2.8521-2.98190.20511260.17522670X-RAY DIFFRACTION100
2.9819-3.13910.25961390.19132632X-RAY DIFFRACTION100
3.1391-3.33570.19751730.18152645X-RAY DIFFRACTION100
3.3357-3.59320.20171250.16492698X-RAY DIFFRACTION100
3.5932-3.95460.21141540.15982623X-RAY DIFFRACTION100
3.9546-4.52630.18041450.15732624X-RAY DIFFRACTION100
4.5263-5.70080.16791560.17522666X-RAY DIFFRACTION100
5.7008-44.7730.17621350.18832658X-RAY DIFFRACTION100
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)
11.2773-0.12840.32022.33990.39871.3498-0.0183-0.0918-0.0172-0.02210.01140.01050.1183-0.11290.00760.2008-0.0220.02310.25410.01940.1819-23.9494-5.450521.038
20.7354-0.17951.95274.0666-3.4267.35620.1809-0.23440.8718-0.57550.0091-0.3833-0.0005-0.1308-0.23270.57150.09870.03080.4054-0.06531.01741.0603-54.779420.1953
31.29130.43280.27723.3589-0.20031.5005-0.02930.1058-0.1956-0.4410.0596-0.04040.29980.0215-0.0220.26110.02250.02860.2501-0.00240.2131-17.707-10.951610.9742
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid -1 through 208 )
2X-RAY DIFFRACTION2chain 'A' and (resid 1001 through 1106 )
3X-RAY DIFFRACTION3chain 'A' and (resid 219 through 305 )

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