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Basic information

Entry
Database: PDB / ID: 2cib
TitleHigh throughput screening and x-ray crystallography assisted evaluation of small molecule scaffolds for CYP51 inhibitors
ComponentsCYTOCHROME P450 51
KeywordsOXIDOREDUCTASE / HEME / HEME LIPID SYNTHESIS / METAL-BINDING / MONOOXYGENASE / NADP / PROTEIN-INHIBITOR COMPLEX / STEROID BIOSYNTHESIS / STEROL BIOSYNTHESIS
Function / homology
Function and homology information


sterol 14alpha-demethylase (ferredoxin) / sterol 14alpha-demethylase / sterol 14-demethylase activity / steroid 7-alpha-hydroxylase activity / oxysterol 7-alpha-hydroxylase activity / sterol biosynthetic process / sterol metabolic process / bile acid biosynthetic process / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen / monooxygenase activity ...sterol 14alpha-demethylase (ferredoxin) / sterol 14alpha-demethylase / sterol 14-demethylase activity / steroid 7-alpha-hydroxylase activity / oxysterol 7-alpha-hydroxylase activity / sterol biosynthetic process / sterol metabolic process / bile acid biosynthetic process / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen / monooxygenase activity / cholesterol homeostasis / oxidoreductase activity / iron ion binding / heme binding / cytoplasm / cytosol
Similarity search - Function
Cytochrome P450, E-class, group IV / Cytochrome p450 / Cytochrome P450 / Cytochrome P450, conserved site / Cytochrome P450 cysteine heme-iron ligand signature. / Cytochrome P450 / Cytochrome P450 superfamily / Cytochrome P450 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-CM6 / PROTOPORPHYRIN IX CONTAINING FE / Lanosterol 14-alpha demethylase / Sterol 14alpha-demethylase
Similarity search - Component
Biological speciesMYCOBACTERIUM TUBERCULOSIS (bacteria)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsPodust, L.M. / Kim, Y. / Yermalitskaya, L.V. / Von Kries, J.P. / Waterman, M.R.
CitationJournal: Antimicrob.Agents Chemother. / Year: 2007
Title: Small Molecule Scaffolds for Cyp51 Inhibitors Identified by High Throughput Screening and Defined by X-Ray Crystallography
Authors: Podust, L.M. / Von Kries, J.P. / Eddine, A.N. / Kim, Y. / Yermalitskaya, L.V. / Kuehne, R. / Ouellet, H. / Warrier, T. / Altekoster, M. / Lee, J.-S. / Rademann, J. / Oschkinat, H. / ...Authors: Podust, L.M. / Von Kries, J.P. / Eddine, A.N. / Kim, Y. / Yermalitskaya, L.V. / Kuehne, R. / Ouellet, H. / Warrier, T. / Altekoster, M. / Lee, J.-S. / Rademann, J. / Oschkinat, H. / Kaufmann, S.H.E. / Waterman, M.R.
History
DepositionMar 17, 2006Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 3, 2007Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3May 8, 2019Group: Data collection / Experimental preparation / Other
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status
Item: _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval
Revision 1.4Dec 13, 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_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 / _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

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Assembly

Deposited unit
A: CYTOCHROME P450 51
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,5193
Polymers51,4771
Non-polymers1,0422
Water6,449358
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)44.937, 85.889, 111.009
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 CYTOCHROME P450 51 / STEROL 14ALPHA-DEMETHYLASE CYP51 / YPLI / P450-LIA1 / STEROL 14-ALPHA DEMETHYLASE / LANOSTEROL 14- ...STEROL 14ALPHA-DEMETHYLASE CYP51 / YPLI / P450-LIA1 / STEROL 14-ALPHA DEMETHYLASE / LANOSTEROL 14-ALPHA DEMETHYLASE / P450-14DM


Mass: 51477.285 Da / Num. of mol.: 1 / Mutation: YES
Source method: isolated from a genetically manipulated source
Details: 4XHIS TAG AT THE C-TERMINUS / Source: (gene. exp.) MYCOBACTERIUM TUBERCULOSIS (bacteria) / Strain: H37RV / Plasmid: PET17B / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): HMS174(DE3)
References: UniProt: P0A512, UniProt: P9WPP9*PLUS, sterol 14alpha-demethylase
#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-CM6 / (2S)-2-[(2,1,3-BENZOTHIADIAZOL-4-YLSULFONYL)AMINO]-2-PHENYL-N-PYRIDIN-4-YLACETAMIDE


Mass: 425.484 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H15N5O3S2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 358 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN A, CYS 37 TO LEU ENGINEERED RESIDUE IN CHAIN A, CYS 442 TO ALA
Sequence detailsMUTATIONS C37L, C442A 4XHIS TAG AT THE C-TERMINUS

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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: 2.09 Å3/Da / Density % sol: 40 % / Description: NONE
Crystal growTemperature: 295 K / pH: 7.5
Details: 30 % PEG 4000, 8 % ISOPROPANOL, 50 MM HEPES, PH=7.5; 2 MM (2S)-2-[(2,1,3-BENZOTHIADIAZOL-4- YLSULFONYL)AMINO]-2-PHENYL-N-PYRIDIN-4-YLACETAMIDE, T=22 C

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID / Wavelength: 0.97933
DetectorType: ADSC CCD / Detector: CCD / Date: Feb 24, 2006 / Details: MIRRORS
RadiationMonochromator: SI (111) DOUBLE CRYSTAL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97933 Å / Relative weight: 1
ReflectionResolution: 1.5→50 Å / Num. obs: 69465 / % possible obs: 98.2 % / Observed criterion σ(I): 0 / Redundancy: 5.5 % / Biso Wilson estimate: 21.2 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 27.5
Reflection shellResolution: 1.5→1.55 Å / Redundancy: 5.1 % / Rmerge(I) obs: 0.55 / Mean I/σ(I) obs: 2.8 / % possible all: 98.4

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Processing

Software
NameVersionClassification
CNS1.1refinement
HKL-2000data reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1X8V

1x8v


Resolution: 1.5→33.97 Å / Rfactor Rfree error: 0.003 / Data cutoff high absF: 256549.4 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.226 6615 10.1 %RANDOM
Rwork0.204 ---
obs0.204 65316 93.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 61.1593 Å2 / ksol: 0.429792 e/Å3
Displacement parametersBiso mean: 24.3 Å2
Baniso -1Baniso -2Baniso -3
1-6.97 Å20 Å20 Å2
2---2.81 Å20 Å2
3----4.16 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.19 Å0.17 Å
Luzzati d res low-5 Å
Luzzati sigma a0.16 Å0.15 Å
Refinement stepCycle: LAST / Resolution: 1.5→33.97 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3327 0 72 358 3757
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.2
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d20.7
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.94
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.041.5
X-RAY DIFFRACTIONc_mcangle_it1.642
X-RAY DIFFRACTIONc_scbond_it1.932
X-RAY DIFFRACTIONc_scangle_it2.92.5
LS refinement shellResolution: 1.5→1.59 Å / Rfactor Rfree error: 0.009 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.272 993 10 %
Rwork0.26 8910 -
obs--86.6 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMWATER_REP.TOP

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