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- PDB-5whr: Discovery of a novel and selective IDO-1 inhibitor PF-06840003 an... -

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Basic information

Entry
Database: PDB / ID: 5whr
TitleDiscovery of a novel and selective IDO-1 inhibitor PF-06840003 and its characterization as a potential clinical candidate.
ComponentsIndoleamine 2,3-dioxygenase 1
KeywordsOXIDOREDUCTASE/Inhibitor / Cancer immunotherapy / Small molecule inhibitor / OXIDOREDUCTASE / OXIDOREDUCTASE-Inhibitor complex
Function / homology
Function and homology information


indoleamine 2,3-dioxygenase / smooth muscle contractile fiber / indoleamine 2,3-dioxygenase activity / positive regulation of chronic inflammatory response / kynurenic acid biosynthetic process / tryptophan 2,3-dioxygenase activity / positive regulation of T cell tolerance induction / tryptophan catabolic process to kynurenine / stereocilium bundle / positive regulation of type 2 immune response ... indoleamine 2,3-dioxygenase / smooth muscle contractile fiber / indoleamine 2,3-dioxygenase activity / positive regulation of chronic inflammatory response / kynurenic acid biosynthetic process / tryptophan 2,3-dioxygenase activity / positive regulation of T cell tolerance induction / tryptophan catabolic process to kynurenine / stereocilium bundle / positive regulation of type 2 immune response / 'de novo' NAD biosynthetic process from tryptophan / Tryptophan catabolism / tryptophan catabolic process / negative regulation of T cell apoptotic process / positive regulation of T cell apoptotic process / swimming behavior / negative regulation of interleukin-10 production / multicellular organismal response to stress / T cell proliferation / negative regulation of T cell proliferation / positive regulation of interleukin-12 production / female pregnancy / response to lipopolysaccharide / electron transfer activity / inflammatory response / heme binding / metal ion binding / cytosol / cytoplasm
Similarity search - Function
Methane Monooxygenase Hydroxylase; Chain G, domain 1 - #480 / Indoleamine 2,3-dioxygenase / Indoleamine 2,3-dioxygenase / Indoleamine 2,3-dioxygenase signature 1. / Indoleamine 2,3-dioxygenase signature 2. / Tryptophan/Indoleamine 2,3-dioxygenase-like / Methane Monooxygenase Hydroxylase; Chain G, domain 1 / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-AOJ / PROTOPORPHYRIN IX CONTAINING FE / Indoleamine 2,3-dioxygenase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.28 Å
AuthorsGreasley, S.E. / Kaiser, S.E. / Feng, J.L. / Stewart, A.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of a Novel and Selective Indoleamine 2,3-Dioxygenase (IDO-1) Inhibitor 3-(5-Fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (EOS200271/PF-06840003) and Its Characterization as a Potential Clinical Candidate.
Authors: Crosignani, S. / Bingham, P. / Bottemanne, P. / Cannelle, H. / Cauwenberghs, S. / Cordonnier, M. / Dalvie, D. / Deroose, F. / Feng, J.L. / Gomes, B. / Greasley, S. / Kaiser, S.E. / Kraus, M. ...Authors: Crosignani, S. / Bingham, P. / Bottemanne, P. / Cannelle, H. / Cauwenberghs, S. / Cordonnier, M. / Dalvie, D. / Deroose, F. / Feng, J.L. / Gomes, B. / Greasley, S. / Kaiser, S.E. / Kraus, M. / Negrerie, M. / Maegley, K. / Miller, N. / Murray, B.W. / Schneider, M. / Soloweij, J. / Stewart, A.E. / Tumang, J. / Torti, V.R. / Van Den Eynde, B. / Wythes, M.
History
DepositionJul 18, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 27, 2017Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Indoleamine 2,3-dioxygenase 1
B: Indoleamine 2,3-dioxygenase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)90,0336
Polymers88,3362
Non-polymers1,6974
Water4,846269
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)85.200, 91.990, 131.120
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Indoleamine 2,3-dioxygenase 1 / / IDO-1 / Indoleamine-pyrrole 2 / 3-dioxygenase


Mass: 44167.805 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IDO1, IDO, INDO / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P14902, indoleamine 2,3-dioxygenase
#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-AOJ / (3R)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione


Mass: 232.210 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H9FN2O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 269 / Source method: isolated from a natural source / Formula: H2O

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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: 2.98 Å3/Da / Density % sol: 58.68 %
Crystal growTemperature: 286 K / Method: vapor diffusion, sitting drop
Details: Hampton Research Peg/Ion screen condition #4 (20% PEG3350, 0.2M Lithium Chloride)

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Data collection

DiffractionMean temperature: 98 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 26, 2015
RadiationMonochromator: ACCEL DCM / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.28→131 Å / Num. obs: 47881 / % possible obs: 100 % / Redundancy: 6.5 % / Biso Wilson estimate: 58.47 Å2 / Rsym value: 0.057 / Net I/σ(I): 17.7
Reflection shellResolution: 2.28→2.63 Å / Redundancy: 6.7 % / Mean I/σ(I) obs: 3.7 / Num. unique obs: 16558 / Rsym value: 0.418 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
autoXDSdata processing
Aimlessdata scaling
MOLREPphasing
RefinementResolution: 2.28→65.56 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.921 / SU R Cruickshank DPI: 0.24 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.243 / SU Rfree Blow DPI: 0.187 / SU Rfree Cruickshank DPI: 0.188
RfactorNum. reflection% reflectionSelection details
Rfree0.228 2257 4.74 %RANDOM
Rwork0.2 ---
obs0.202 47663 99.9 %-
Displacement parametersBiso mean: 59.34 Å2
Baniso -1Baniso -2Baniso -3
1-14.8053 Å20 Å20 Å2
2---6.0919 Å20 Å2
3----8.7134 Å2
Refine analyzeLuzzati coordinate error obs: 0.31 Å
Refinement stepCycle: 1 / Resolution: 2.28→65.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5870 0 120 269 6259
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.016163HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.088401HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2073SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes141HARMONIC2
X-RAY DIFFRACTIONt_gen_planes951HARMONIC5
X-RAY DIFFRACTIONt_it6163HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion2.78
X-RAY DIFFRACTIONt_other_torsion18.43
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion761SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact7213SEMIHARMONIC4
LS refinement shellResolution: 2.28→2.34 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2659 160 4.63 %
Rwork0.2273 3297 -
all0.2291 3457 -
obs--100 %

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