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- PDB-8otn: structure of InhA from mycobacterium tuberculosis in complex with... -

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Basic information

Entry
Database: PDB / ID: 8otn
Titlestructure of InhA from mycobacterium tuberculosis in complex with inhibitor 7-((1-(3-Hydroxy-4-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-methyl-2H-chromen-2-one
ComponentsEnoyl-[acyl-carrier-protein] reductase [NADH]
KeywordsOXIDOREDUCTASE / enoyl-ACP-reductase type II fatty acid synthase mycolic acids tuberculosis therapeutic target
Function / homology
Function and homology information


trans-2-enoyl-CoA reductase (NADH) activity / mycolic acid biosynthetic process / fatty acid elongation / enoyl-[acyl-carrier-protein] reductase (NADH) / enoyl-[acyl-carrier-protein] reductase (NADH) activity / NAD+ binding / peptidoglycan-based cell wall / fatty acid binding / response to antibiotic / plasma membrane
Similarity search - Function
Enoyl-[acyl-carrier-protein] reductase (NADH) / Enoyl-(Acyl carrier protein) reductase / NAD(P)-binding domain superfamily
Similarity search - Domain/homology
NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Chem-VZR / Enoyl-[acyl-carrier-protein] reductase [NADH]
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.962 Å
AuthorsChebaiki, M. / Maveyraud, L. / Tamhaev, R. / Lherbet, C. / Mourey, L.
Funding support France, 3items
OrganizationGrant numberCountry
Centre National de la Recherche Scientifique (CNRS) France
Universite de Toulouse France
Other government France
CitationJournal: Eur.J.Med.Chem. / Year: 2023
Title: Discovery of new diaryl ether inhibitors against Mycobacterium tuberculosis targeting the minor portal of InhA.
Authors: Chebaiki, M. / Delfourne, E. / Tamhaev, R. / Danoun, S. / Rodriguez, F. / Hoffmann, P. / Grosjean, E. / Goncalves, F. / Azema-Despeyroux, J. / Pal, A. / Kordulakova, J. / Preuilh, N. / ...Authors: Chebaiki, M. / Delfourne, E. / Tamhaev, R. / Danoun, S. / Rodriguez, F. / Hoffmann, P. / Grosjean, E. / Goncalves, F. / Azema-Despeyroux, J. / Pal, A. / Kordulakova, J. / Preuilh, N. / Britton, S. / Constant, P. / Marrakchi, H. / Maveyraud, L. / Mourey, L. / Lherbet, C.
History
DepositionApr 21, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 16, 2023Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Enoyl-[acyl-carrier-protein] reductase [NADH]
B: Enoyl-[acyl-carrier-protein] reductase [NADH]
C: Enoyl-[acyl-carrier-protein] reductase [NADH]
D: Enoyl-[acyl-carrier-protein] reductase [NADH]
hetero molecules


Theoretical massNumber of molelcules
Total (without water)119,82412
Polymers115,3484
Non-polymers4,4768
Water5,873326
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area18360 Å2
ΔGint-127 kcal/mol
Surface area31460 Å2
Unit cell
Length a, b, c (Å)70.156, 91.184, 164.219
Angle α, β, γ (deg.)90, 90, 90
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein
Enoyl-[acyl-carrier-protein] reductase [NADH] / ENR / Enoyl-ACP reductase / FAS-II enoyl-ACP reductase / NADH-dependent 2-trans-enoyl-ACP reductase


Mass: 28837.057 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Gene: inhA, Rv1484, MTCY277.05
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P9WGR1, enoyl-[acyl-carrier-protein] reductase (NADH)
#2: Chemical
ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Nicotinamide adenine dinucleotide


Mass: 663.425 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: C21H27N7O14P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: NAD*YM
#3: Chemical
ChemComp-VZR / 4-methyl-7-[[1-[(3-oxidanyl-4-phenoxy-phenyl)methyl]-1,2,3-triazol-4-yl]methoxy]chromen-2-one


Mass: 455.462 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C26H21N3O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 326 / Source method: isolated from a natural source / Formula: H2O
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: 2.32 Å3/Da / Density % sol: 46.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.8
Details: 14 % PEG 4000 100 mM ADA 100 mM ammonium acetate 5 % DMSO pH 6.8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.97625 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Mar 1, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.962→82.109 Å / Num. obs: 55487 / % possible obs: 89.1 % / Redundancy: 4.62 %
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: 0.995 / CC1/2 anomalous: -0.117 / Rmerge(I) obs: 0.1371 / Rpim(I) all: 0.0698 / Rrim(I) all: 0.1544 / AbsDiff over sigma anomalous: 0.764 / Baniso tensor eigenvalue 1: 0.5037 Å2 / Baniso tensor eigenvalue 2: 0 Å2 / Baniso tensor eigenvalue 3: 12.4447 Å2 / Baniso tensor eigenvector 1 ortho1: 1 / Baniso tensor eigenvector 1 ortho2: 0 / Baniso tensor eigenvector 1 ortho3: 0 / Baniso tensor eigenvector 2 ortho1: 0 / Baniso tensor eigenvector 2 ortho2: 1 / Baniso tensor eigenvector 2 ortho3: 0 / Baniso tensor eigenvector 3 ortho1: 0 / Baniso tensor eigenvector 3 ortho2: 0 / Baniso tensor eigenvector 3 ortho3: 1 / Aniso diffraction limit 1: 1.962 Å / Aniso diffraction limit 2: 1.979 Å / Aniso diffraction limit 3: 2.43 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): 8.55 / Num. measured all: 256508 / Observed signal threshold: 1.2 / Orthogonalization convention: pdb / % possible anomalous: 86.2 / % possible ellipsoidal: 89.1 / % possible ellipsoidal anomalous: 86.2 / % possible spherical: 72.9 / % possible spherical anomalous: 70.3 / Redundancy anomalous: 2.46 / 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
6.063-82.1094.40.046720.931219012190277327730.998-0.2940.02450.0530.64296.99996.99996.92.5199
4.777-6.0634.810.065418.31334513345277627760.996-0.1410.03320.07370.72899.199.599.199.599.12.5999.5
4.155-4.7774.690.06319.471301213012277427740.995-0.1810.03210.0710.76697.199.297.199.297.12.5299.2
3.768-4.1554.890.073118.071356313563277327730.995-0.2220.03650.0820.76298.399.498.399.498.32.699.4
3.49-3.7685.010.093115.291390813908277627760.993-0.1370.04590.10420.79898.699.598.699.598.62.6499.5
3.281-3.494.90.121312.361357513575277327730.989-0.1360.06080.13610.81399.199.699.199.699.12.5899.6
3.114-3.2815.010.148710.531389113891277527750.983-0.0640.0730.16620.78298.399.798.399.798.32.6499.7
2.976-3.1145.070.20768.31407314073277427740.965-0.0210.10160.23180.7899.599.799.599.799.52.6599.7
2.859-2.9765.270.24267.521461314613277427740.962-0.0450.11630.26970.79299.610099.610099.62.75100
2.759-2.8595.290.29166.541468714687277627760.941-0.0230.14030.32450.77699.699.999.699.999.62.7699.9
2.671-2.7595.290.36335.351467314673277427740.912-0.0480.17430.4040.7729999.99999.9992.7799.9
2.594-2.6714.750.42684.771315913159277327730.841-0.0190.21790.48090.81397.899.797.899.797.82.4999.7
2.524-2.5934.890.50294.021356913569277627760.845-0.0190.2480.56250.74298.699.798.699.798.62.5699.7
2.46-2.5244.70.60153.291304613046277427740.797-0.0610.30230.67550.74295.997.595.997.595.92.4797.5
2.395-2.464.310.53033.451195811958277227720.8170.0070.28060.60240.76184.487.684.486.583.62.2987.6
2.331-2.3954.240.51693.381176311763277727770.793-0.010.27690.5890.74483.587.283.579.476.82.2487.2
2.268-2.3314.060.58993.021127511275277427740.751-0.0410.32170.6750.75181.185.981.171.167.92.1685.9
2.17-2.2683.510.69272.397389738277327730.705-0.0170.39620.80240.74548.256.348.240.234.8256.3
2.098-2.173.770.74132.251047510475277627760.628-0.0280.42160.8570.7569.774.369.746.944.42.0274.3
1.962-2.0983.61.02251.8399959995277427740.4680.0280.6041.1940.79243.347.543.320.318.71.9347.5

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Processing

Software
NameVersionClassification
BUSTER2.10.4 (8-JUN-2022)refinement
XDSdata reduction
autoPROCdata processing
Aimlessdata scaling
BUSTER2.10.4 (8-JUN-2022)phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.962→28.5 Å / Cor.coef. Fo:Fc: 0.932 / Cor.coef. Fo:Fc free: 0.916 / SU R Cruickshank DPI: 0.267 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.271 / SU Rfree Blow DPI: 0.197 / SU Rfree Cruickshank DPI: 0.199
RfactorNum. reflection% reflectionSelection details
Rfree0.233 2855 -RANDOM
Rwork0.1944 ---
obs0.1964 55464 72.9 %-
Displacement parametersBiso mean: 29.25 Å2
Baniso -1Baniso -2Baniso -3
1-2.5876 Å20 Å20 Å2
2---1.552 Å20 Å2
3----1.0356 Å2
Refine analyzeLuzzati coordinate error obs: 0.25 Å
Refinement stepCycle: LAST / Resolution: 1.962→28.5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7859 0 312 326 8497
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0088415HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9611508HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2830SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes1597HARMONIC5
X-RAY DIFFRACTIONt_it8415HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion1131SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies14HARMONIC1
X-RAY DIFFRACTIONt_ideal_dist_contact8505SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.39
X-RAY DIFFRACTIONt_other_torsion16.07
LS refinement shellResolution: 1.962→2.04 Å
RfactorNum. reflection% reflection
Rfree0.3261 55 -
Rwork0.2634 --
obs--13.19 %
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)
10.55640.0108-0.07880.6240.01380.3957-0.0381-0.0147-0.0564-0.01470.0005-0.0202-0.0564-0.02020.0376-0.0942-0.0021-0.0162-0.1870.0008-0.14455.86324.266757.7339
20.55470.1932-0.11160.64780.16380.4742-0.0214-0.0320.0607-0.0320.01450.02930.06070.02930.0069-0.0990.0120.0021-0.18560.0056-0.164711.7749-18.966456.8659
30.6232-0.0406-0.21811.0638-0.05060.5951-0.01430.12670.01070.1267-0.0011-0.01220.0107-0.01220.0154-0.11370.00640.0172-0.1717-0.0038-0.2059-3.4650.60778.3567
40.6926-0.0282-0.07490.84530.19290.48390.0133-0.0372-0.0168-0.03720.01620.1013-0.01680.1013-0.0296-0.1702-0.01550.0077-0.1766-0.0002-0.130532.5015.938354.1877
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A3 - 269
2X-RAY DIFFRACTION1{ A|* }A301 - 302
3X-RAY DIFFRACTION2{ B|* }B1 - 268
4X-RAY DIFFRACTION2{ B|* }B301 - 302
5X-RAY DIFFRACTION3{ C|* }C3 - 269
6X-RAY DIFFRACTION3{ C|* }C301 - 302
7X-RAY DIFFRACTION4{ D|* }D3 - 269
8X-RAY DIFFRACTION4{ D|* }D301 - 302

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