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- PDB-8s53: X-ray crystal structure of CYP142 from Mycobacterium tuberculosis... -

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Basic information

Entry
Database: PDB / ID: 8s53
TitleX-ray crystal structure of CYP142 from Mycobacterium tuberculosis in complex with a fragment bound in two poses
ComponentsSteroid C26-monooxygenase
KeywordsOXIDOREDUCTASE / CYP142 / P450 / cholesterol / cytochrome / tuberculosis / fragment / heme / CYP / iron / drug
Function / homology
Function and homology information


cholesterol 26-hydroxylase activity / cholest-4-en-3-one 26-monooxygenase [(25R)-3-oxocholest-4-en-26-oate forming] / cholest-4-en-3-one 26-monooxygenase activity / steroid hydroxylase activity / cholesterol catabolic process / peptidoglycan-based cell wall / iron ion binding / heme binding
Similarity search - Function
Cytochrome P450, B-class / Cytochrome P450, conserved site / Cytochrome P450 cysteine heme-iron ligand signature. / Cytochrome P450 / Cytochrome P450 superfamily / Cytochrome P450
Similarity search - Domain/homology
4-benzylpyridine / PROTOPORPHYRIN IX CONTAINING FE / Steroid C26-monooxygenase
Similarity search - Component
Biological speciesMycobacterium tuberculosis H37Rv (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsSnee, M. / Kavanagh, M. / Levy, C. / Leys, D.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Biotechnology and Biological Sciences Research Council (BBSRC) United Kingdom
Citation
Journal: Biorxiv / Year: 2024
Title: Fragment-based development of small molecule inhibitors targeting Mycobacterium tuberculosis cholesterol metabolism.
Authors: Kavanagh, M.E. / McLean, K.J. / Gilbert, S.H. / Amadi, C. / Snee, M. / Tunnicliffe, R.B. / Arora, K. / Boshoff, H.I. / Fanourakis, A. / Rebello-Lopez, M.J. / Ortega-Muro, F. / Levy, C.W. / ...Authors: Kavanagh, M.E. / McLean, K.J. / Gilbert, S.H. / Amadi, C. / Snee, M. / Tunnicliffe, R.B. / Arora, K. / Boshoff, H.I. / Fanourakis, A. / Rebello-Lopez, M.J. / Ortega-Muro, F. / Levy, C.W. / Munro, A.W. / Leys, D. / Abell, C. / Coyne, A.G.
#1: Journal: Acta Crystallogr., Sect. D: Biol. Crystallogr. / Year: 2019
Title: Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix
Authors: Liebschner, D. / Afonine, P. / Baker, M.
History
DepositionFeb 22, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 29, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Steroid C26-monooxygenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,5724
Polymers46,6171
Non-polymers9553
Water7,656425
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1200 Å2
ΔGint-26 kcal/mol
Surface area16040 Å2
Unit cell
Length a, b, c (Å)55.458, 65.772, 130.655
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein Steroid C26-monooxygenase / Cholest-4-en-3-one C26-monooxygenase / Cholest-4-en-3-one C26-monooxygenase [(25R)-3-oxocholest-4- ...Cholest-4-en-3-one C26-monooxygenase / Cholest-4-en-3-one C26-monooxygenase [(25R)-3-oxocholest-4-en-26-oate forming] / Cholesterol C26-monooxygenase / Cholesterol C26-monooxygenase [(25R)-3beta-hydroxycholest-5-en-26-oate forming] / Cytochrome P450 142 / Steroid C27-monooxygenase


Mass: 46616.746 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis H37Rv (bacteria)
Gene: cyp142, cyp142A1, Rv3518c, MTV023.25c / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): C41
References: UniProt: P9WPL5, cholest-4-en-3-one 26-monooxygenase [(25R)-3-oxocholest-4-en-26-oate forming]
#2: Chemical ChemComp-3QO / 4-benzylpyridine


Mass: 169.222 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H11N / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 425 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.56 Å3/Da / Density % sol: 51.87 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop
Details: 10% PEG 550MME WITH 100 MM POTASSIUM THIOCYANATE AND 0.1 M SODIUM ACETATE AT A PH RANGE OF 5.0-6.0.

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Data collection

DiffractionMean temperature: 99 K / Ambient temp details: N2 cryostream / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.92 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jun 10, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 1.6→65.77 Å / Num. obs: 62563 / % possible obs: 97.9 % / Redundancy: 7.8 % / Biso Wilson estimate: 24.61 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.062 / Rpim(I) all: 0.023 / Rrim(I) all: 0.066 / Net I/σ(I): 17
Reflection shellResolution: 1.6→1.63 Å / Rmerge(I) obs: 0.831 / Mean I/σ(I) obs: 1.3 / Num. unique obs: 2491 / CC1/2: 0.657 / Rpim(I) all: 0.39 / Rrim(I) all: 0.925

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
DIALSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→65.33 Å / SU ML: 0.1757 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 16.3619
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1749 3120 4.99 %
Rwork0.1562 59363 -
obs0.1571 62483 97.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 32.11 Å2
Refinement stepCycle: LAST / Resolution: 1.6→65.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3071 0 64 425 3560
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01163234
X-RAY DIFFRACTIONf_angle_d1.15364407
X-RAY DIFFRACTIONf_chiral_restr0.0638485
X-RAY DIFFRACTIONf_plane_restr0.0136584
X-RAY DIFFRACTIONf_dihedral_angle_d7.7624471
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.6-1.630.22031130.23022151X-RAY DIFFRACTION79.36
1.63-1.650.25651440.21932304X-RAY DIFFRACTION85.56
1.65-1.680.24361300.23092478X-RAY DIFFRACTION90.62
1.68-1.710.26391400.24172595X-RAY DIFFRACTION96.88
1.71-1.740.30941300.2822752X-RAY DIFFRACTION99.9
1.74-1.780.22681560.24012715X-RAY DIFFRACTION99.97
1.78-1.820.2481290.20132743X-RAY DIFFRACTION99.97
1.82-1.860.20971430.17532717X-RAY DIFFRACTION100
1.86-1.910.16091290.14922761X-RAY DIFFRACTION99.97
1.91-1.960.16941330.14432728X-RAY DIFFRACTION100
1.96-2.020.17991430.1542731X-RAY DIFFRACTION100
2.02-2.080.18811530.16552739X-RAY DIFFRACTION100
2.08-2.160.20181390.17632757X-RAY DIFFRACTION100
2.16-2.240.17281620.13452726X-RAY DIFFRACTION100
2.24-2.340.14531320.12842772X-RAY DIFFRACTION100
2.34-2.470.13911430.13622742X-RAY DIFFRACTION100
2.47-2.620.16911330.13922801X-RAY DIFFRACTION99.97
2.62-2.820.19931380.14932765X-RAY DIFFRACTION100
2.82-3.110.15771560.15572790X-RAY DIFFRACTION99.97
3.11-3.560.19071660.15562784X-RAY DIFFRACTION100
3.56-4.480.14081560.1332834X-RAY DIFFRACTION100
4.48-65.330.16831520.16292978X-RAY DIFFRACTION99.71
Refinement TLS params.Method: refined / Origin x: 15.2656435981 Å / Origin y: -11.4137079102 Å / Origin z: -17.5817235028 Å
111213212223313233
T0.149856788238 Å2-0.000522536466275 Å20.0120551019352 Å2-0.158330900138 Å20.00117760871682 Å2--0.111949660139 Å2
L1.09331412997 °2-0.296788069688 °20.388230881605 °2-1.46287027988 °2-0.192030334079 °2--1.17225359972 °2
S-0.0560713875308 Å °0.0351766668585 Å °0.0252162723463 Å °0.0425986598878 Å °0.0129613622763 Å °-0.0682393401165 Å °0.00280572675941 Å °0.144733383601 Å °0.037249297829 Å °
Refinement TLS groupSelection details: all

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