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- PDB-6x10: Crystal structure of acetyltransferase Eis from Mycobacterium tub... -

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Basic information

Entry
Database: PDB / ID: 6x10
TitleCrystal structure of acetyltransferase Eis from Mycobacterium tuberculosis in complex with haloperidol
ComponentsN-acetyltransferase Eis
KeywordsTRANSFERASE/TRANSFERASE Inhibitor / Aminoglycoside / Drug resistance / Repurposing / Acetylation / Inhibitor / TRANSFERASE / TRANSFERASE-TRANSFERASE Inhibitor complex
Function / homology
Function and homology information


effector-mediated defense to host-produced reactive oxygen species / symbiont-mediated perturbation of host inflammatory response / symbiont-mediated suppression of host defense-related programmed cell death / aminoglycoside antibiotic catabolic process / aminoglycoside N-acetyltransferase activity / symbiont-mediated perturbation of host innate immune response / Suppression of autophagy / symbiont-mediated perturbation of host programmed cell death / bacterial extracellular vesicle / biological process involved in interaction with host ...effector-mediated defense to host-produced reactive oxygen species / symbiont-mediated perturbation of host inflammatory response / symbiont-mediated suppression of host defense-related programmed cell death / aminoglycoside antibiotic catabolic process / aminoglycoside N-acetyltransferase activity / symbiont-mediated perturbation of host innate immune response / Suppression of autophagy / symbiont-mediated perturbation of host programmed cell death / bacterial extracellular vesicle / biological process involved in interaction with host / host cell cytoplasmic vesicle / N-acetyltransferase activity / peptide-lysine-N-acetyltransferase activity / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / host extracellular space / response to antibiotic / identical protein binding / cytosol
Similarity search - Function
N-acetyltransferase Eis / Enhanced intracellular survival protein domain / Eis-like, acetyltransferase domain / Sterol carrier protein domain / Acetyltransferase (GNAT) domain / Acetyltransferase (GNAT) domain / SCP2 sterol-binding domain superfamily / Gcn5-related N-acetyltransferase (GNAT) domain profile. / GNAT domain / Acyl-CoA N-acyltransferase
Similarity search - Domain/homology
Chem-GMJ / N-acetyltransferase Eis
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.03 Å
AuthorsPunetha, A. / Garneau-Tsodikova, S. / Tsodikov, O.V.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI090048 United States
CitationJournal: Rsc Med Chem / Year: 2021
Title: Structure-based design of haloperidol analogues as inhibitors of acetyltransferase Eis from Mycobacterium tuberculosis to overcome kanamycin resistance
Authors: Punetha, A. / Green, K.D. / Garzan, A. / Willby, M.J. / Pang, A.H. / Hou, C. / Holbrook, S.Y.L. / Krieger, K. / Posey, J.E. / Parish, T. / Tsodikov, O.V. / Garneau-Tsodikova, S.
History
DepositionMay 17, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 2, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 24, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: N-acetyltransferase Eis
hetero molecules


Theoretical massNumber of molelcules
Total (without water)46,6999
Polymers45,9991
Non-polymers7008
Water5,585310
1
A: N-acetyltransferase Eis
hetero molecules
x 6


Theoretical massNumber of molelcules
Total (without water)280,19454
Polymers275,9956
Non-polymers4,20048
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-y,x-y,z1
crystal symmetry operation3_555-x+y,-x,z1
crystal symmetry operation4_556y,x,-z+11
crystal symmetry operation5_556x-y,-y,-z+11
crystal symmetry operation6_556-x,-x+y,-z+11
Buried area29400 Å2
ΔGint-303 kcal/mol
Surface area87240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)175.177, 175.177, 123.402
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number155
Space group name H-MH32
Components on special symmetry positions
IDModelComponents
11A-905-

HOH

21A-907-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein N-acetyltransferase Eis / Aminoglycoside N-acetyltransferase / Enhanced intracellular survival protein / Protein-lysine N- ...Aminoglycoside N-acetyltransferase / Enhanced intracellular survival protein / Protein-lysine N-acetyltransferase


Mass: 45999.113 Da / Num. of mol.: 1 / Mutation: C204A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) (bacteria)
Strain: ATCC 25618 / H37Rv / Gene: eis, Rv2416c, MTCY253.04 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P9WFK7, Transferases; Acyltransferases; Transferring groups other than aminoacyl groups

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Non-polymers , 5 types, 318 molecules

#2: Chemical ChemComp-GMJ / 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)butan-1-one


Mass: 375.864 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H23ClFNO2 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, antipsychotic*YM
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 310 / 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: 3.96 Å3/Da / Density % sol: 68.95 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.1 M Tris-HCl pH 8.5, 13% PEG 8000 and 0.4 M (NH4)2SO4, kanamycin KAN (10 mM) and CoA (8 mM)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Jul 11, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.02→50 Å / Num. obs: 44763 / % possible obs: 94 % / Observed criterion σ(I): 2.1 / Redundancy: 4 % / CC1/2: 0.97 / Net I/σ(I): 12
Reflection shellResolution: 2.02→2.07 Å / Redundancy: 3.3 % / Num. unique obs: 3788 / CC1/2: 0.829

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3R1K

3r1k


Resolution: 2.03→37.26 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.952 / SU B: 3.317 / SU ML: 0.089 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.128 / ESU R Free: 0.121 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2009 2173 5 %RANDOM
Rwork0.1751 ---
obs0.1764 41606 93.45 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 79.05 Å2 / Biso mean: 32.061 Å2 / Biso min: 19.76 Å2
Baniso -1Baniso -2Baniso -3
1--1.2 Å2-0.6 Å20 Å2
2---1.2 Å20 Å2
3---3.88 Å2
Refinement stepCycle: final / Resolution: 2.03→37.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3026 0 37 310 3373
Biso mean--61.39 44.76 -
Num. residues----391
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0133128
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172932
X-RAY DIFFRACTIONr_angle_refined_deg1.3371.6544248
X-RAY DIFFRACTIONr_angle_other_deg1.2131.5746716
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7425388
X-RAY DIFFRACTIONr_dihedral_angle_2_deg25.63218.743183
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.1315482
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.2131541
X-RAY DIFFRACTIONr_chiral_restr0.0580.2398
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023551
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02744
LS refinement shellResolution: 2.03→2.083 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.261 193 -
Rwork0.244 3112 -
all-3305 -
obs--96.55 %

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