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- PDB-4uvg: Discovery of pyrimidine isoxazoles InhA in complex with compound 15 -

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Basic information

Entry
Database: PDB / ID: 4uvg
TitleDiscovery of pyrimidine isoxazoles InhA in complex with compound 15
ComponentsENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADH]
KeywordsOXIDOREDUCTASE / INHA / ACP ENOYL REDUCTASE / FBLG / PYRIMIDINE ISOXAZOLE
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 / 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-A0C / 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 / MOLECULAR REPLACEMENT / Resolution: 1.92 Å
AuthorsRead, J.A. / Gingell, H. / Madhavapeddi, P. / Ghorpade, S. / Cowan, S.
CitationJournal: To be Published
Title: Hitting the Target in More Than One Way: Novel, Direct Inhibitors of Mycobacterium Tuberculosis Enoyl Acp Reductase
Authors: Madhavapeddi, P. / Kale, R.R. / Cowen, S.D. / Ghorpade, S.R. / Davies, G. / Bellale, E.V. / Kale, M.G. / Srivastava, A. / Spadola, L. / Kawatkar, A. / Raichurkar, A.V. / Tonge, M. / ...Authors: Madhavapeddi, P. / Kale, R.R. / Cowen, S.D. / Ghorpade, S.R. / Davies, G. / Bellale, E.V. / Kale, M.G. / Srivastava, A. / Spadola, L. / Kawatkar, A. / Raichurkar, A.V. / Tonge, M. / Nandishaiah, R. / Guptha, S. / Narayan, A. / Gingell, H. / Plant, D. / Landge, S. / Menasinakai, S. / Prabhakar, K.R. / Achar, V. / Ambady, A. / Sambandamurthy, V.K. / Ramachandran, V. / Panduga, V. / Reddy, J. / Kumar, C.N.N. / Kaur, P. / Shandil, R. / Iyer, P.S. / Narayanan, S. / Read, J.A.
History
DepositionAug 5, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 30, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.2Jan 10, 2024Group: 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 / pdbx_struct_conn_angle / struct_conn / 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 / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _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
A: ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADH]
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,7455
Polymers28,5551
Non-polymers1,1904
Water5,711317
1
A: ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADH]
hetero molecules

A: ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADH]
hetero molecules

A: ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADH]
hetero molecules

A: ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADH]
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,98020
Polymers114,2194
Non-polymers4,76116
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_555x,x-y,-z+1/31
crystal symmetry operation4_765-x+2,-y+1,z1
crystal symmetry operation9_765-x+2,-x+y+1,-z+1/31
Buried area21280 Å2
ΔGint-176.5 kcal/mol
Surface area32190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)96.229, 96.229, 139.841
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number180
Space group name H-MP6222

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Components

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Protein , 1 types, 1 molecules A

#1: Protein ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADH] / ENOYL-ACYL CARRIER PROTEIN REDUCTASE


Mass: 28554.781 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) MYCOBACTERIUM TUBERCULOSIS (bacteria) / Strain: H37RV / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / Variant (production host): STAR
References: UniProt: M9TGV3, UniProt: P9WGR1*PLUS, enoyl-[acyl-carrier-protein] reductase (NADH)

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Non-polymers , 5 types, 321 molecules

#2: Chemical ChemComp-NAD / NICOTINAMIDE-ADENINE-DINUCLEOTIDE


Mass: 663.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H27N7O14P2 / Comment: NAD*YM
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400


Mass: 238.278 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#5: Chemical ChemComp-A0C / 5-[(4,6-dimethylpyrimidin-2-yl)sulfanylmethyl]isoxazole-3-carboxamide


Mass: 264.304 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C11H12N4O2S
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 317 / 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: 3.27 Å3/Da / Density % sol: 65.42 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E / Wavelength: 1.5418
DetectorType: RIGAKU CCD / Detector: CCD / Date: Dec 5, 2012 / Details: MIRRORS
RadiationMonochromator: NI FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.92→41.7 Å / Num. obs: 29667 / % possible obs: 99.3 % / Observed criterion σ(I): 2 / Redundancy: 7.6 % / Biso Wilson estimate: 22.5 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 13.5
Reflection shellResolution: 1.92→2.02 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.42 / Mean I/σ(I) obs: 2.6 / % possible all: 95.7

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Processing

Software
NameVersionClassification
BUSTER2.11.2refinement
XDSdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4D0R

4d0r


Resolution: 1.92→41.67 Å / Cor.coef. Fo:Fc: 0.9491 / Cor.coef. Fo:Fc free: 0.9376 / SU R Cruickshank DPI: 0.107 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.12 / SU Rfree Blow DPI: 0.109 / SU Rfree Cruickshank DPI: 0.102
RfactorNum. reflection% reflectionSelection details
Rfree0.1883 1505 5.08 %RANDOM
Rwork0.1626 ---
obs0.1639 29624 99.13 %-
Displacement parametersBiso mean: 23.48 Å2
Baniso -1Baniso -2Baniso -3
1--1.9266 Å20 Å20 Å2
2---1.9266 Å20 Å2
3---3.8531 Å2
Refinement stepCycle: LAST / Resolution: 1.92→41.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1975 0 79 317 2371
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012102HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.012862HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d713SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes43HARMONIC2
X-RAY DIFFRACTIONt_gen_planes330HARMONIC5
X-RAY DIFFRACTIONt_it2102HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.52
X-RAY DIFFRACTIONt_other_torsion14.61
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion282SEMIHARMONIC5
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_contact2783SEMIHARMONIC4
LS refinement shellResolution: 1.92→1.99 Å / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.2164 148 5.48 %
Rwork0.1981 2553 -
all0.1991 2701 -
obs--99.13 %
Refinement TLS params.Method: refined / Origin x: 51.1675 Å / Origin y: 47.1933 Å / Origin z: 18.2738 Å
111213212223313233
T-0.0479 Å20.0072 Å2-0.013 Å2-0.0216 Å2-0.0179 Å2---0.0225 Å2
L0.4774 °2-0.0593 °20.0649 °2-0.3536 °20.0754 °2--0.6178 °2
S-0.0356 Å °0.0397 Å °0.0226 Å °-0.0019 Å °-0.0308 Å °0.0727 Å °-0.0651 Å °-0.1651 Å °0.0664 Å °
Refinement TLS groupSelection details: CHAIN A

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