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Basic information

Entry
Database: PDB / ID: 4cod
TitleEncoded library technology as a source of hits for the discovery and lead optimization of a potent and selective class of bactericidal direct inhibitors of Mycobacterium tuberculosis InhA
ComponentsENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADH]
KeywordsTRANSFERASE / ELT / ENCODED LIBRARY TECHNOLOGY / ISONIAZID / L-PROLINE
Function / homology
Function and homology information


enoyl-[acyl-carrier-protein] reductase activity (NAD(P)H) / 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 / fatty acid biosynthetic process ...enoyl-[acyl-carrier-protein] reductase activity (NAD(P)H) / 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 / fatty acid biosynthetic process / response to antibiotic / plasma membrane
Similarity search - Function
Enoyl-[acyl-carrier-protein] reductase (NADH) / Enoyl-(Acyl carrier protein) reductase / NAD(P)-binding Rossmann-like Domain / NAD(P)-binding domain superfamily / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-KV1 / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Enoyl-[acyl-carrier-protein] reductase [NADH] / Enoyl-[acyl-carrier-protein] reductase [NADH]
Similarity search - Component
Biological speciesMYCOBACTERIUM TUBERCULOSIS (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsEncinas, L. / OKeefe, H. / Neu, M. / Convery, M.A. / McDowell, W. / Mendoza-Losana, A. / Pages, L.B. / Castro-Pichel, J. / Evindar, G.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Encoded Library Technology as a Source of Hits for the Discovery and Lead Optimization of a Potent and Selective Class of Bactericidal Direct Inhibitors of Mycobacterium Tuberculosis Inha.
Authors: Encinas, L. / O'Keefe, H. / Neu, M. / Remuinan, M.J. / Patel, A.M. / Guardia, A. / Davie, C.P. / Perez-Macias, N. / Yang, H. / Convery, M.A. / Messer, J.A. / Perez-Herran, E. / Centrella, P. ...Authors: Encinas, L. / O'Keefe, H. / Neu, M. / Remuinan, M.J. / Patel, A.M. / Guardia, A. / Davie, C.P. / Perez-Macias, N. / Yang, H. / Convery, M.A. / Messer, J.A. / Perez-Herran, E. / Centrella, P.A. / Alvarez-Gomez, D. / Clark, M.A. / Huss, S. / O'Donovan, G.K. / Ortega-Muro, F. / Mcdowell, W. / Castaneda, P. / Arico-Muendel, C.C. / Pajk, S. / Rullas, J. / Angulo-Barturen, I. / Alvarez-Ruiz, E. / Mendoza-Losana, A. / Pages, L.B. / Castro-Pichel, J. / Evindar, G.
History
DepositionJan 28, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 12, 2014Provider: repository / Type: Initial release
Revision 1.1Mar 12, 2014Group: Database references
Revision 1.2Mar 19, 2014Group: Refinement description
Revision 1.3Jun 11, 2014Group: Refinement description
Revision 1.4Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADH]
D: ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADH]
F: ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADH]
H: ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADH]
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,62312
Polymers114,2194
Non-polymers4,4048
Water6,918384
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area14590 Å2
ΔGint-97.6 kcal/mol
Surface area34190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)100.180, 102.350, 179.360
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
ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADH] / NADH-DEPENDENT ENOYL-ACP REDUCTASE / ENOYL-ACYL CARRIER PROT EIN REDUCTASE


Mass: 28554.781 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) MYCOBACTERIUM TUBERCULOSIS (bacteria) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P0A5Y6, UniProt: P9WGR1*PLUS, enoyl-[acyl-carrier-protein] reductase (NADH)
#2: Chemical
ChemComp-KV1 / N-((3R,5S)-1-(benzofuran-3-carbonyl)-5-(ethylcarbamoyl)pyrrolidin-3-yl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide


Mass: 437.492 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H27N5O4
#3: Chemical
ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE / Nicotinamide adenine dinucleotide


Mass: 663.425 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 384 / 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: 4.03 Å3/Da / Density % sol: 69.44 %
Description: RMERG FOR HIGH RESOLUTION SHELL IS 1.977. DATA IS VERY ANISOTROPIC. DATA USED IN REFINEMENT HAS BEEN TRUNCATED TO 3.2A IN THE A* DIRECTION
Crystal growpH: 8.5
Details: 10% PEG 8K, 0.1M TRIS PH8.5 25% ETHYLENE GLYCOL USED AS CRYO.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.976
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Oct 7, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.4→102.6 Å / Num. obs: 72859 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 7.2 % / Biso Wilson estimate: 71.11 Å2 / Rmerge(I) obs: 0.16 / Net I/σ(I): 10.3
Reflection shellResolution: 2.4→2.53 Å / Redundancy: 7 % / Rmerge(I) obs: 1.5 / Mean I/σ(I) obs: 1 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2H7I

2h7i
PDB Unreleased entry


Resolution: 2.4→35.14 Å / Cor.coef. Fo:Fc: 0.9351 / Cor.coef. Fo:Fc free: 0.917 / SU R Cruickshank DPI: 0.325 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.334 / SU Rfree Blow DPI: 0.226 / SU Rfree Cruickshank DPI: 0.226
RfactorNum. reflection% reflectionSelection details
Rfree0.2064 2636 5.09 %RANDOM
Rwork0.1703 ---
obs0.1722 51787 71.18 %-
Displacement parametersBiso mean: 62.84 Å2
Baniso -1Baniso -2Baniso -3
1-15.9029 Å20 Å20 Å2
2---8.2567 Å20 Å2
3----7.6462 Å2
Refine analyzeLuzzati coordinate error obs: 0.337 Å
Refinement stepCycle: LAST / Resolution: 2.4→35.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7984 0 304 384 8672
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.018468HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.2211544HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2884SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes180HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1244HARMONIC5
X-RAY DIFFRACTIONt_it8468HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.03
X-RAY DIFFRACTIONt_other_torsion20.05
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1132SEMIHARMONIC5
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_contact10068SEMIHARMONIC4
LS refinement shellResolution: 2.4→2.46 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.4865 41 4.83 %
Rwork0.2469 808 -
all0.2561 849 -
obs--71.18 %
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)
10.3604-0.6158-0.17491.0766-0.06460.6029-0.1330.1580.0483-0.25360.2145-0.02170.03820.1458-0.08160.3276-0.08830.1187-0.17670.0221-0.22595.637471.8831-66.6096
20.468-0.17040.22841.73220.45031.3511-0.0310.07320.1146-0.11310.1255-0.1142-0.34890.2203-0.09450.2876-0.06980.0816-0.23140.0099-0.23128.754192.1428-57.7411
30.7616-0.0544-0.27891.630.22781.1881-0.0890.0798-0.1189-0.2050.10950.05630.4232-0.0473-0.02060.3619-0.04930.099-0.2943-0.0224-0.26732.225449.7883-65.5754
40.57080.08970.0691.39530.13631.6853-0.16820.22330.0271-0.32360.16650.3980.0044-0.31430.00170.2453-0.0818-0.0395-0.20.0674-0.2178-15.786275.704-71.5917
50.2771-0.0044-0.10791.3811-0.1251.1249-0.17770.1619-0.0404-0.2640.2352-0.45470.00020.5121-0.05750.1379-0.0740.2051-0.0711-0.1131-0.188527.284669.7493-71.5323
60.6248-0.8104-0.21641.4890.79351.1857-0.00890.08980.0307-0.0840.17010.07720.06860.1519-0.16120.1533-0.08650.1369-0.13690.0462-0.12185.63771.841-66.6008
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{B AND RESEQ 1271}, {D AND RESEQ 1271}, {F AND RESEQ 1270}, {H AND RESEQ 1271}
2X-RAY DIFFRACTION2{ B|2 - B|269 }
3X-RAY DIFFRACTION3{ D|2 - B|269 } }
4X-RAY DIFFRACTION4{ F|2 - B|269 }
5X-RAY DIFFRACTION5{ H|2 - B|269 }
6X-RAY DIFFRACTION6{B AND RESEQ 1270}, {D AND RESEQ 1270}, {F AND RESEQ 1271}, {H AND RESEQ 1270}

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