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- PDB-7m7d: Crystal structure of the indoleamine 2,3-dioxygenagse 1 (IDO1) co... -

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Basic information

Entry
Database: PDB / ID: 7m7d
TitleCrystal structure of the indoleamine 2,3-dioxygenagse 1 (IDO1) complexed with IACS-8968
ComponentsIndoleamine 2,3-dioxygenase 1
KeywordsHYDROLASE/HYDROLASE INHIBITOR / IDO1 / Inhibitor / Enzyme / Complex / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


indoleamine 2,3-dioxygenase / positive regulation of chronic inflammatory response / smooth muscle contractile fiber / indoleamine 2,3-dioxygenase activity / kynurenic acid biosynthetic process / tryptophan 2,3-dioxygenase activity / positive regulation of T cell tolerance induction / L-tryptophan catabolic process to kynurenine / quinolinate biosynthetic process / stereocilium bundle ... indoleamine 2,3-dioxygenase / positive regulation of chronic inflammatory response / smooth muscle contractile fiber / indoleamine 2,3-dioxygenase activity / kynurenic acid biosynthetic process / tryptophan 2,3-dioxygenase activity / positive regulation of T cell tolerance induction / L-tryptophan catabolic process to kynurenine / quinolinate biosynthetic process / stereocilium bundle / 'de novo' NAD+ biosynthetic process from L-tryptophan / positive regulation of type 2 immune response / L-tryptophan catabolic process / negative regulation of T cell apoptotic process / Tryptophan catabolism / 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
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
Similarity search - Domain/homology
PROTOPORPHYRIN IX CONTAINING FE / Chem-YRM / Indoleamine 2,3-dioxygenase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsLeonard, P.G. / Cross, J.B.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of IACS-9779 and IACS-70465 as Potent Inhibitors Targeting Indoleamine 2,3-Dioxygenase 1 (IDO1) Apoenzyme.
Authors: Hamilton, M.M. / Mseeh, F. / McAfoos, T.J. / Leonard, P.G. / Reyna, N.J. / Harris, A.L. / Xu, A. / Han, M. / Soth, M.J. / Czako, B. / Theroff, J.P. / Mandal, P.K. / Burke, J.P. / Virgin- ...Authors: Hamilton, M.M. / Mseeh, F. / McAfoos, T.J. / Leonard, P.G. / Reyna, N.J. / Harris, A.L. / Xu, A. / Han, M. / Soth, M.J. / Czako, B. / Theroff, J.P. / Mandal, P.K. / Burke, J.P. / Virgin-Downey, B. / Petrocchi, A. / Pfaffinger, D. / Rogers, N.E. / Parker, C.A. / Yu, S.S. / Jiang, Y. / Krapp, S. / Lammens, A. / Trevitt, G. / Tremblay, M.R. / Mikule, K. / Wilcoxen, K. / Cross, J.B. / Jones, P. / Marszalek, J.R. / Lewis, R.T.
History
DepositionMar 27, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 1, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Oct 30, 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

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)94,5866
Polymers92,5912
Non-polymers1,9964
Water1267
1
A: Indoleamine 2,3-dioxygenase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,2933
Polymers46,2951
Non-polymers9982
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Indoleamine 2,3-dioxygenase 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,2933
Polymers46,2951
Non-polymers9982
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)85.860, 91.790, 128.780
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

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


Mass: 46295.258 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 BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P14902, indoleamine 2,3-dioxygenase
#2: Chemical ChemComp-YRM / (5S)-6,6-dimethyl-8-[(4S)-7-(trifluoromethyl)imidazo[1,5-a]pyridin-5-yl]-1,3,8-triazaspiro[4.5]decane-2,4-dione


Mass: 381.352 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H18F3N5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 7 / Source method: isolated from a natural source / Formula: H2O
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: 2.74 Å3/Da / Density % sol: 55.12 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 100 mM Tris pH 8.0, 18% (w/v) PEG6000, 0.2 M NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Feb 4, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→91.79 Å / Num. obs: 32045 / % possible obs: 100 % / Redundancy: 14.4 % / CC1/2: 0.996 / Rmerge(I) obs: 0.167 / Rpim(I) all: 0.046 / Rrim(I) all: 0.174 / Net I/σ(I): 9.8 / Num. measured all: 460177 / Scaling rejects: 993
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.6-2.7214.52.4555588338410.7250.6652.5441.5100
9.01-91.7911.30.09999298780.9930.0290.10319.699.8

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Processing

Software
NameVersionClassification
MOSFLM7.2.2data reduction
Aimless0.7.1data scaling
PHASER2.8.1phasing
PHENIX1.19.1-4122-000refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5ETW

5etw


Resolution: 2.6→33.29 Å / SU ML: 0.4112 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.9792
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2352 1609 5.04 %
Rwork0.2088 30344 -
obs0.2101 31953 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 85.15 Å2
Refinement stepCycle: LAST / Resolution: 2.6→33.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5919 0 140 7 6066
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.016216
X-RAY DIFFRACTIONf_angle_d0.59528452
X-RAY DIFFRACTIONf_chiral_restr0.0364904
X-RAY DIFFRACTIONf_plane_restr0.00421063
X-RAY DIFFRACTIONf_dihedral_angle_d15.0242276
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6-2.680.43031520.36942721X-RAY DIFFRACTION99.97
2.68-2.780.36621660.33392681X-RAY DIFFRACTION99.89
2.78-2.890.34531350.2972697X-RAY DIFFRACTION99.96
2.89-3.020.31941300.27912745X-RAY DIFFRACTION99.97
3.02-3.180.32651380.27972741X-RAY DIFFRACTION100
3.18-3.380.30291310.27812766X-RAY DIFFRACTION100
3.38-3.640.27351690.23362711X-RAY DIFFRACTION99.97
3.64-4.010.25091260.1922783X-RAY DIFFRACTION99.97
4.01-4.590.19131420.17232777X-RAY DIFFRACTION100
4.59-5.770.20361710.17262793X-RAY DIFFRACTION100
5.77-33.290.16861490.17262929X-RAY DIFFRACTION99.81
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)
15.71703686957-0.449433404392.625431301662.89264631081-0.376792649385.9531672249-0.221696358882-0.8692846614660.418143921231-0.000228282917917-0.2469785523630.642808406288-0.159877916696-1.420833797510.3684296581440.5159929050270.0884317542303-0.05316658999060.668781737829-0.2930143584230.697607672911-46.3445451037-25.2172228998-25.7708861695
25.58363087348-1.592718764593.795460463841.54766104838-1.028897314074.810746296270.1438271048910.125890815531-0.0653280199256-0.212915933626-0.2043070889880.03079783069380.360889434140.1211000381970.01052527961710.4840455927250.0889140361382-0.01338989596520.378935896574-0.09998570158350.476645760938-29.1890960328-30.3587652638-25.4464182597
35.21235306594-0.3574342734413.823278966922.63753986252-0.2683175764754.28991238455-0.02418350010630.4956253875190.186249220234-0.0965855683677-0.177414893862-0.1317493308450.1007660198530.5554927655090.3094295265760.4595060299260.0573134237835-0.02681181625850.435248653651-0.01107905340660.43365512532-20.0256018273-28.2743901992-24.2176130262
46.351745498045.058863078874.176576327485.242839573342.026734335868.819263986760.6506277429591.636842974430.138947765834-0.763584605628-0.920186429025-1.077353381580.2141851491841.96956418428-0.02295721698430.667249142890.2399558315690.1238842599771.40860741650.004582442653320.501270986087-13.2436341075-29.6596008325-31.611906883
56.038073864070.604425300109-0.8091732830123.70307765981-1.226018633492.557008063640.0564770529354-0.147599144318-0.1128586367710.0807747167849-0.579877888309-0.914951163925-0.2241441197421.876036184630.389026533480.571816052829-0.136084844027-0.08807195619641.520663921240.1869332609150.795321727257-0.937595389153-0.191135232182-15.3895032132
65.957854801380.982008853934-2.958804175711.8217840718-0.9174930675834.805520156680.03945727982120.1789894022650.469949400952-0.0618091110971-0.02187820039830.0101241717077-0.2860227034050.707834384559-0.005929825778490.520737872062-0.145535060857-0.06598999424520.7108912794770.01392802616260.412011955202-18.61640304931.70235869976-13.0258434341
74.47023050590.0459865936306-1.395780618782.69234471106-0.4595173102454.69175026874-0.1776180627620.763925363766-0.1665241263980.118216274256-0.01156795707260.1574217993170.162305367796-0.2062813244590.2043706590230.410507636834-0.1257094109290.0006737148199730.596022197666-0.03013296538610.440192321576-27.3232999983-1.59874280498-13.9794221994
86.370505911293.39296656994-0.4487153929943.60004982221-2.99020035384.28880834928-0.1649438362422.003505005670.853983946903-0.404932730280.6174039085560.80590070847-0.424598139836-1.35874000245-0.6513645761370.576559470651-0.00878647056482-0.04992183108410.876717812040.1454467387630.670682605375-33.00348809683.09542497211-20.7446925755
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 11 through 159 )AA11 - 1591 - 149
22chain 'A' and (resid 160 through 258 )AA160 - 258150 - 248
33chain 'A' and (resid 259 through 361 )AA259 - 361249 - 351
44chain 'A' and (resid 383 through 402 )AA383 - 402352 - 371
55chain 'B' and (resid 11 through 159 )BE11 - 1591 - 149
66chain 'B' and (resid 160 through 258 )BE160 - 258150 - 248
77chain 'B' and (resid 259 through 362 )BE259 - 362249 - 352
88chain 'B' and (resid 380 through 401 )BE380 - 401353 - 374

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