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

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Basic information

Entry
Database: PDB / ID: 8otm
Titlestructure of InhA from mycobacterium tuberculosis in complex with N-((1-(3-hydroxy-4-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-oxo-2H-chromene-3-carboxamide
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
ACETATE ION / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Chem-VZI / Enoyl-[acyl-carrier-protein] reductase [NADH]
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.6 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
La Region Occitanie 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)119,68321
Polymers114,7964
Non-polymers4,88817
Water19,6001088
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area20050 Å2
ΔGint-164 kcal/mol
Surface area32160 Å2
Unit cell
Length a, b, c (Å)90.588, 92.784, 90.751
Angle α, β, γ (deg.)90, 119.2, 90
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 4 molecules ABCD

#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: 28698.912 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)

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Non-polymers , 6 types, 1105 molecules

#2: Chemical
ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Nicotinamide adenine dinucleotide


Mass: 663.425 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: NAD*YM
#3: Chemical
ChemComp-VZI / 2-oxidanylidene-~{N}-[[1-[(3-oxidanyl-4-phenoxy-phenyl)methyl]-1,2,3-triazol-4-yl]methyl]chromene-3-carboxamide


Mass: 468.461 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C26H20N4O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Na
#6: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1088 / 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: 2.91 Å3/Da / Density % sol: 57.8 %
Crystal growTemperature: 285 K / Method: vapor diffusion, sitting drop / pH: 6.8
Details: 14 % PEG 4000 100 mM ADA 100 mM acetate ammonium, pH 6.8, 5 % DMSO

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALBA / Beamline: XALOC / Wavelength: 0.97926 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 4, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97926 Å / Relative weight: 1
ReflectionResolution: 1.6→79.072 Å / Num. obs: 157530 / % possible obs: 96.8 % / Redundancy: 5.67 %
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: 0.999 / CC1/2 anomalous: -0.183 / Rmerge(I) obs: 0.0723 / Rpim(I) all: 0.0332 / Rrim(I) all: 0.0798 / AbsDiff over sigma anomalous: 0.703 / Baniso tensor eigenvalue 1: 8.1193 Å2 / Baniso tensor eigenvalue 2: 0.4501 Å2 / Baniso tensor eigenvalue 3: 0 Å2 / Baniso tensor eigenvector 1 ortho1: 0.9699 / Baniso tensor eigenvector 1 ortho2: 0 / Baniso tensor eigenvector 1 ortho3: -0.2435 / Baniso tensor eigenvector 2 ortho1: 0 / Baniso tensor eigenvector 2 ortho2: 1 / Baniso tensor eigenvector 2 ortho3: 0 / Baniso tensor eigenvector 3 ortho1: 0.2435 / Baniso tensor eigenvector 3 ortho2: 0 / Baniso tensor eigenvector 3 ortho3: 0.9699 / Aniso diffraction limit 1: 1.74 Å / Aniso diffraction limit 2: 1.561 Å / Aniso diffraction limit 3: 1.569 Å / Aniso diffraction limit axis 1 ortho1: 0.99764 / Aniso diffraction limit axis 1 ortho2: 0 / Aniso diffraction limit axis 1 ortho3: -0.0682 / 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: 0.0682 / Aniso diffraction limit axis 3 ortho2: 0 / Aniso diffraction limit axis 3 ortho3: 0.99764 / Net I/σ(I): 13.45 / Num. measured all: 892498 / Observed signal threshold: 1.2 / Orthogonalization convention: pdb / % possible anomalous: 96.2 / % possible ellipsoidal: 96.8 / % possible ellipsoidal anomalous: 96.2 / % possible spherical: 91.3 / % possible spherical anomalous: 90.9 / Redundancy anomalous: 2.88 / 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
4.499-79.0725.620.028241.714423544235787678760.999-0.2730.01290.03110.6679999.59999.5992.9299.5
3.566-4.4995.530.033139.364357443574787678760.998-0.2690.01530.03660.71598.999.698.999.698.92.8399.6
3.111-3.5665.760.042732.284533645336787778770.998-0.2390.01930.0470.73599.199.799.199.799.12.9499.7
2.825-3.1115.650.057325.064453344533787678760.996-0.1730.02640.06330.7529999.79999.7992.8999.7
2.622-2.8255.70.070520.584489844898787878780.995-0.1680.03260.07790.76799.499.799.499.799.42.999.7
2.466-2.6225.890.089816.844641146411787778770.993-0.1040.04070.09880.75199.199.799.199.799.12.9999.7
2.342-2.4665.720.098415.184500645006787378730.992-0.1020.04530.10870.7429999.69999.6992.9199.6
2.239-2.3425.850.11813.194611746117787878780.989-0.0860.05370.130.75499.399.699.399.699.32.9799.6
2.152-2.2395.560.132911.294376743767787778770.986-0.0760.06230.14720.73699.299.799.299.799.22.8299.7
2.078-2.1525.840.16899.414601746017787678760.981-0.0750.07690.1860.70599.199.799.199.799.12.9699.7
2.012-2.0785.920.2018.164665646656787678760.973-0.0820.09080.22110.7079999.59999.599399.5
1.954-2.0125.820.233874584345843787878780.965-0.0470.10660.25760.7059999.59999.5992.9599.5
1.903-1.9545.740.28025.874523145231787678760.951-0.0190.12840.3090.6889999.59999.5992.9299.5
1.856-1.9035.80.34314.894566145661787678760.933-0.050.15640.3780.6739999.59999.5992.9499.5
1.813-1.8565.610.40064.094423844238787978790.9070.0020.18620.44310.65798.699.198.699.198.62.8599.1
1.774-1.8135.820.4913.54585245852787778770.878-0.010.22330.54070.66797.397.697.397.697.32.9497.6
1.734-1.7745.840.53173.194598245982787378730.868-0.0280.24120.58520.66289.989.789.989.589.72.9589.7
1.694-1.7345.720.5722.884509245092787778770.836-0.0130.26120.63030.65387.287.687.280.280.12.987.6
1.652-1.6945.210.59722.494105841058787878780.797-0.0190.28680.66460.66387.688.487.668.968.62.6488.4
1.6-1.6524.70.6472.053699136991787678760.716-0.0290.32950.72920.65882.383.382.350.249.82.3983.3

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Processing

Software
NameVersionClassification
BUSTER2.10.4 (8-JUN-2022)refinement
autoPROC1.0.5 20220608data processing
XDSJan 10, 2022data reduction
Aimless0.7.9data scaling
STARANISO2.3.87data scaling
BUSTER2.10.4 (8-JUN-2022)phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.6→79.07 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.961 / SU R Cruickshank DPI: 0.074 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.078 / SU Rfree Blow DPI: 0.074 / SU Rfree Cruickshank DPI: 0.072
RfactorNum. reflection% reflectionSelection details
Rfree0.1775 8312 -RANDOM
Rwork0.1586 ---
obs0.1596 157530 91.3 %-
Displacement parametersBiso mean: 21.91 Å2
Baniso -1Baniso -2Baniso -3
1-0.8482 Å20 Å2-0.0748 Å2
2---0.2824 Å20 Å2
3----0.5659 Å2
Refine analyzeLuzzati coordinate error obs: 0.17 Å
Refinement stepCycle: LAST / Resolution: 1.6→79.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7885 0 337 1088 9310
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0098785HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.9512006HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3003SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes1702HARMONIC5
X-RAY DIFFRACTIONt_it8785HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion1163SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies36HARMONIC1
X-RAY DIFFRACTIONt_ideal_dist_contact9572SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion4.1
X-RAY DIFFRACTIONt_other_torsion13.9
LS refinement shellResolution: 1.6→1.62 Å
RfactorNum. reflection% reflection
Rfree0.2504 176 -
Rwork0.2171 --
obs0.2191 3151 42.25 %
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)
10.3237-0.03720.03280.57060.02860.41960.01220.01140.06330.01140.0184-0.01720.0633-0.0172-0.03060.006-0.0083-0.0104-0.03430.005-0.029819.00251.212422.3138
20.4327-0.0347-0.08260.8689-0.00640.44970.0116-0.10830.0092-0.10830.00410.06190.00920.0619-0.0158-0.02440.0060.0257-0.0158-0.0212-0.02443.876619.045411.8926
30.3474-0.0122-0.03110.5897-0.00330.3958-0.01580.0001-0.05380.00010.02150.0155-0.05380.0155-0.00570.0083-0.00150.0081-0.0321-0.0008-0.041325.647843.806821.4729
40.3789-0.04870.11810.9183-0.0250.46950.0085-0.10870.0042-0.10870.0036-0.07020.0042-0.0702-0.0122-0.03680.0025-0.0274-0.01350.0188-0.01070.998525.330711.0376
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A2 - 269
2X-RAY DIFFRACTION1{ A|* }A301 - 304
3X-RAY DIFFRACTION2{ B|* }B2 - 269
4X-RAY DIFFRACTION2{ B|* }B301 - 303
5X-RAY DIFFRACTION3{ C|* }C3 - 269
6X-RAY DIFFRACTION3{ C|* }C301 - 303
7X-RAY DIFFRACTION4{ D|* }D3 - 268
8X-RAY DIFFRACTION4{ D|* }D301 - 302

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