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- PDB-8s4m: Crystal structure of Mycobacterium tuberculosis cytochrome P450 C... -

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Basic information

Entry
Database: PDB / ID: 8s4m
TitleCrystal structure of Mycobacterium tuberculosis cytochrome P450 CYP125 in complex with an inhibitor
ComponentsSteroid C26-monooxygenase
KeywordsOXIDOREDUCTASE / CYP125 / tuberculosis / cholesterol / P450 / CYP / cytochrome / fragment / cholestenone
Function / homology
Function and homology information


cholest-4-en-3-one 26-monooxygenase [(25S)-3-oxocholest-4-en-26-oate forming] / cholest-4-en-3-one 26-monooxygenase activity / biological process involved in interaction with host / steroid hydroxylase activity / cholesterol catabolic process / iron ion binding / heme binding
Similarity search - Function
Cytochrome P450, B-class / Cytochrome P450 / Cytochrome P450 superfamily / Cytochrome P450
Similarity search - Domain/homology
: / PROTOPORPHYRIN IX CONTAINING FE / Steroid C26-monooxygenase
Similarity search - Component
Biological speciesMycobacterium tuberculosis H37Rv (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsSnee, M. / Kavanagh, M. / Levy, C.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Biotechnology and Biological Sciences Research Council (BBSRC) United Kingdom
Citation
Journal: J.Med.Chem. / Year: 2025
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.N. / Snee, M. / Tunnicliffe, R.B. / Arora, K. / Boshoff, H.I.M. / Fanourakis, A. / Rebollo-Lopez, M.J. / Ortega, F. / Levy, C.W. / ...Authors: Kavanagh, M.E. / McLean, K.J. / Gilbert, S.H. / Amadi, C.N. / Snee, M. / Tunnicliffe, R.B. / Arora, K. / Boshoff, H.I.M. / Fanourakis, A. / Rebollo-Lopez, M.J. / Ortega, F. / Levy, C.W. / Munro, A.W. / Leys, D. / Abell, C. / Coyne, A.G.
#1: 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.
#2: Journal: Acta Crystallogr., Sect. D: Biol. Crystallogr. / Year: 2012
Title: Towards automated crystallographic structure refinement with phenix.refine.
Authors: Afonine, P. / Grosse-Kunstleve, R. / Echols, N.
History
DepositionFeb 21, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 29, 2025Provider: repository / Type: Initial release
Revision 1.1Jul 30, 2025Group: Database references / Category: citation / citation_author
Revision 1.2Aug 6, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Steroid C26-monooxygenase
B: Steroid C26-monooxygenase
C: Steroid C26-monooxygenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)143,14317
Polymers139,9903
Non-polymers3,15214
Water5,909328
1
A: Steroid C26-monooxygenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,8568
Polymers46,6631
Non-polymers1,1937
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Steroid C26-monooxygenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,3763
Polymers46,6631
Non-polymers7132
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Steroid C26-monooxygenase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)47,9106
Polymers46,6631
Non-polymers1,2475
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)136.899, 68.848, 144.124
Angle α, β, γ (deg.)90.000, 93.915, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z

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Components

#1: Protein Steroid C26-monooxygenase / Cholest-4-en-3-one 26-monooxygenase / Cholest-4-en-3-one C26-monooxygenase [(25S)-3-oxocholest-4-en- ...Cholest-4-en-3-one 26-monooxygenase / Cholest-4-en-3-one C26-monooxygenase [(25S)-3-oxocholest-4-en-26-oate forming] / Cholesterol C26-monooxygenase / Cholesterol C26-monooxygenase [(25S)-3beta-hydroxycholest-5-en-26-oate forming] / Cytochrome P450 125 / Steroid C27-monooxygenase


Mass: 46663.383 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis H37Rv (bacteria)
Gene: cyp125, cyp125A1, Rv3545c, MTCY03C7.11 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): C41
References: UniProt: P9WPP1, cholest-4-en-3-one 26-monooxygenase [(25S)-3-oxocholest-4-en-26-oate forming]
#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-A1H47 / ~{N}-(1~{H}-indol-5-ylmethyl)-3-(pyridin-4-ylamino)benzamide


Mass: 342.394 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H18N4O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 328 / 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: 2.42 Å3/Da / Density % sol: 49.19 % / Description: chunks
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 6.2 / Details: 1.9 M Ammonium sulphate, 0.1M MES pH 6.2 / PH range: 6-6.5 / Temp details: 4C

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: N2 cryostream / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.9159 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 7, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9159 Å / Relative weight: 1
ReflectionResolution: 2.1→68.29 Å / Num. obs: 78300 / % possible obs: 99.9 % / Redundancy: 3.3 % / Biso Wilson estimate: 38.76 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.071 / Rpim(I) all: 0.046 / Rrim(I) all: 0.084 / Net I/σ(I): 9.1
Reflection shellResolution: 2.1→2.14 Å / Rmerge(I) obs: 0.861 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 4463 / CC1/2: 0.585 / Rpim(I) all: 0.545 / Rrim(I) all: 1.022

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→68.29 Å / SU ML: 0.2739 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 27.2907
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2458 3941 5.04 %
Rwork0.212 74313 -
obs0.2137 78254 99.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 59.24 Å2
Refinement stepCycle: LAST / Resolution: 2.1→68.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9549 0 205 328 10082
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.003110078
X-RAY DIFFRACTIONf_angle_d0.618913733
X-RAY DIFFRACTIONf_chiral_restr0.03961400
X-RAY DIFFRACTIONf_plane_restr0.0051817
X-RAY DIFFRACTIONf_dihedral_angle_d7.921382
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.130.35781480.32092664X-RAY DIFFRACTION99.86
2.13-2.150.32611570.31042596X-RAY DIFFRACTION100
2.15-2.180.33461250.29052650X-RAY DIFFRACTION100
2.18-2.210.31791260.29882657X-RAY DIFFRACTION100
2.21-2.240.37321340.36712613X-RAY DIFFRACTION99.49
2.24-2.280.40051500.37012616X-RAY DIFFRACTION99.42
2.28-2.310.34581310.27512688X-RAY DIFFRACTION99.79
2.31-2.350.2631360.27512595X-RAY DIFFRACTION99.85
2.35-2.390.2841330.26642709X-RAY DIFFRACTION99.89
2.39-2.430.3191610.26982564X-RAY DIFFRACTION99.93
2.43-2.480.33911410.26782655X-RAY DIFFRACTION99.86
2.48-2.530.25481510.24932646X-RAY DIFFRACTION99.79
2.53-2.590.26171360.2432620X-RAY DIFFRACTION99.82
2.59-2.650.24451380.23032685X-RAY DIFFRACTION99.61
2.65-2.710.29261300.23872584X-RAY DIFFRACTION99.67
2.71-2.790.25041420.23012665X-RAY DIFFRACTION100
2.79-2.870.29471530.23292656X-RAY DIFFRACTION100
2.87-2.960.29131320.24642663X-RAY DIFFRACTION99.96
2.96-3.070.29751570.25952642X-RAY DIFFRACTION99.89
3.07-3.190.31131350.24022667X-RAY DIFFRACTION99.86
3.19-3.330.25621330.22572670X-RAY DIFFRACTION99.82
3.33-3.510.22121170.20092639X-RAY DIFFRACTION99.89
3.51-3.730.2651290.1982688X-RAY DIFFRACTION100
3.73-4.020.19041330.17432699X-RAY DIFFRACTION99.79
4.02-4.420.18471430.15222665X-RAY DIFFRACTION99.86
4.42-5.060.18321660.15612658X-RAY DIFFRACTION99.96
5.06-6.370.20391530.1812703X-RAY DIFFRACTION99.96
6.38-68.290.21411510.16742756X-RAY DIFFRACTION99.59
Refinement TLS params.Method: refined / Origin x: 29.5723410479 Å / Origin y: -4.46821048012 Å / Origin z: 37.7477922759 Å
111213212223313233
T0.367292729253 Å20.0639934344981 Å2-0.00695606709357 Å2-0.307361159074 Å20.0201065663367 Å2--0.387226509511 Å2
L0.162589867087 °2-0.0313186632211 °2-0.42353317906 °2-0.207502258036 °20.326248206845 °2--1.82219763406 °2
S-0.0740223724223 Å °-0.0150287770435 Å °-0.010230259035 Å °-0.149227798619 Å °0.0507553103954 Å °-0.0602235654593 Å °0.22100011887 Å °0.271971084775 Å °0.026390723765 Å °
Refinement TLS groupSelection details: all

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