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- PDB-5frb: Crystal structure of sterol 14-alpha demethylase (CYP51B) from a ... -

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Basic information

Entry
Database: PDB / ID: 5frb
TitleCrystal structure of sterol 14-alpha demethylase (CYP51B) from a pathogenic filamentous fungus Aspergillus fumigatus in complex with a tetrazole-based inhibitor VT-1598
ComponentsSTEROL 14-ALPHA DEMETHYLASE, CYP51B
KeywordsOXIDOREDUCTASE / STEROL 14-ALPHA DEMETHYLASE (CYP51) / CYTOCHROME P450 / HEME / MONOOXYGENASE / STEROL BIOSYNTHESIS / EUKARYOTIC MEMBRANES / CYTOCHROME P450 FOLD / ENDOPLASMIC RETICULUM MEMBRANE / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR COMPLEX
Function / homology
Function and homology information


ergosterol biosynthetic process / sterol 14-demethylase activity / sterol 14alpha-demethylase / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen / membrane => GO:0016020 / methyltransferase activity / monooxygenase activity / methylation / oxidoreductase activity / iron ion binding ...ergosterol biosynthetic process / sterol 14-demethylase activity / sterol 14alpha-demethylase / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen / membrane => GO:0016020 / methyltransferase activity / monooxygenase activity / methylation / oxidoreductase activity / iron ion binding / heme binding / endoplasmic reticulum membrane
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
PROTOPORPHYRIN IX CONTAINING FE / Chem-VT2 / 14-alpha sterol demethylase Cyp51B / Sterol 14-alpha demethylase cyp51B
Similarity search - Component
Biological speciesASPERGILLUS FUMIGATUS (mold)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.99 Å
AuthorsHargrove, T.Y. / Wawrzak, Z. / Lepesheva, G.I.
CitationJournal: Antimicrob. Agents Chemother. / Year: 2017
Title: Crystal Structure of the New Investigational Drug Candidate VT-1598 in Complex with Aspergillus fumigatus Sterol 14 alpha-Demethylase Provides Insights into Its Broad-Spectrum Antifungal Activity.
Authors: Hargrove, T.Y. / Garvey, E.P. / Hoekstra, W.J. / Yates, C.M. / Wawrzak, Z. / Rachakonda, G. / Villalta, F. / Lepesheva, G.I.
History
DepositionDec 16, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 26, 2017Provider: repository / Type: Initial release
Revision 1.1May 10, 2017Group: Database references
Revision 1.2May 17, 2017Group: Database references
Revision 1.3Jul 5, 2017Group: Database references / Category: citation
Item: _citation.country / _citation.journal_id_ASTM ..._citation.country / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_volume / _citation.title
Revision 1.4Jan 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 / 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_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: STEROL 14-ALPHA DEMETHYLASE, CYP51B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,7843
Polymers53,5811
Non-polymers1,2032
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)109.857, 109.857, 84.838
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121

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Components

#1: Protein STEROL 14-ALPHA DEMETHYLASE, CYP51B


Mass: 53581.266 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, RESIDUES 50-519 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) ASPERGILLUS FUMIGATUS (mold) / Gene: ERG 11 / Plasmid: PCW / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): HMS174
References: UniProt: A0A0J5PJX1, UniProt: E9QY26*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-VT2 / (R)-4-((4-((6-(2-(2,4-difluorophenyl)-1,1-difluoro-2-hydroxy-3-(1H-tetrazol-1-yl)propyl)pyridin-3-yl)ethynyl)phenoxy)methyl)benzonitrile


Mass: 586.539 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H22F4N6O2

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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: 2.77 Å3/Da / Density % sol: 55.6 % / Description: NONE
Crystal growpH: 7.4 / Details: pH 7.4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97856
DetectorType: MARRESEARCH / Detector: CCD / Date: Sep 25, 2015 / Details: BE LENSES DIAMOND LAUE
RadiationMonochromator: DIAMOND / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97856 Å / Relative weight: 1
ReflectionResolution: 2.99→95.15 Å / Num. obs: 12238 / % possible obs: 99.7 % / Observed criterion σ(I): 2 / Redundancy: 5.4 % / Biso Wilson estimate: 116.3 Å2 / Rmerge(I) obs: 0.03 / Net I/σ(I): 26.1
Reflection shellResolution: 2.99→3.07 Å / Redundancy: 5.6 % / Rmerge(I) obs: 0.65 / Mean I/σ(I) obs: 1.9 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.8.0131refinement
MOSFLMdata reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4UHL

4uhl


Resolution: 2.99→95.14 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.936 / SU B: 67.354 / SU ML: 0.523 / Cross valid method: THROUGHOUT / ESU R Free: 0.496 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.28006 674 5.6 %RANDOM
Rwork0.25839 ---
obs0.25955 11467 99.22 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 153.732 Å2
Baniso -1Baniso -2Baniso -3
1-0.19 Å20.09 Å20 Å2
2--0.19 Å2-0 Å2
3----0.61 Å2
Refinement stepCycle: LAST / Resolution: 2.99→95.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3752 0 86 0 3838
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.023951
X-RAY DIFFRACTIONr_bond_other_d00.023700
X-RAY DIFFRACTIONr_angle_refined_deg0.7541.9885378
X-RAY DIFFRACTIONr_angle_other_deg0.5263.0028523
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7995469
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.39423.237173
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.80215648
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.141525
X-RAY DIFFRACTIONr_chiral_restr0.0470.2573
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0214418
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02936
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it14.54411.5971879
X-RAY DIFFRACTIONr_mcbond_other14.54711.5931878
X-RAY DIFFRACTIONr_mcangle_it20.41417.4572347
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it14.30212.2562072
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.995→3.072 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.359 62 -
Rwork0.339 813 -
obs--97.77 %
Refinement TLS params.Method: refined / Origin x: 293.3559 Å / Origin y: 16.6827 Å / Origin z: 8.3265 Å
111213212223313233
T0.4704 Å20.1908 Å2-0.1167 Å2-0.1971 Å2-0.1747 Å2--0.3436 Å2
L1.1223 °2-0.3911 °20.0508 °2-1.8984 °2-0.5923 °2--0.2513 °2
S0.5967 Å °0.1397 Å °-0.0702 Å °-0.2405 Å °-0.311 Å °0.7588 Å °0.0858 Å °0.1768 Å °-0.2858 Å °

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