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- PDB-6cr2: Crystal structure of sterol 14-alpha demethylase (CYP51B) from As... -

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Basic information

Entry
Database: PDB / ID: 6cr2
TitleCrystal structure of sterol 14-alpha demethylase (CYP51B) from Aspergillus fumigatus in complex with the VNI derivative N-(1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-(2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl)-1,3,4-oxadiazol-2-yl)benzamide
Components14-alpha sterol demethylase Cyp51B
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR / sterol 14-alpha demethylase (CYP51) / cytochrome P450 fold / OXIDOREDUCTASE-OXIDOREDUCTASE INHIBITOR complex
Function / homology
Function and homology information


ergosterol biosynthetic process / sterol 14alpha-demethylase / sterol 14-demethylase activity / methyltransferase activity / methylation / oxidoreductase activity / iron ion binding / heme binding / endoplasmic reticulum membrane
Similarity search - Function
: / Cytochrome P450, E-class, group IV / Cytochrome P450, conserved site / Cytochrome P450 cysteine heme-iron ligand signature. / Cytochrome P450 / Cytochrome P450 superfamily / Cytochrome P450
Similarity search - Domain/homology
PROTOPORPHYRIN IX CONTAINING FE / Chem-LFV / Sterol 14-alpha demethylase cyp51B
Similarity search - Component
Biological speciesAspergillus fumigatus (mold)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.38 Å
AuthorsFriggeri, L. / Hargrove, T.Y. / Wawrzak, Z. / Lepesheva, G.I.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01067871 United States
CitationJournal: J. Med. Chem. / Year: 2018
Title: Sterol 14 alpha-Demethylase Structure-Based Design of VNI (( R)- N-(1-(2,4-Dichlorophenyl)-2-(1 H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide)) Derivatives To Target Fungal ...Title: Sterol 14 alpha-Demethylase Structure-Based Design of VNI (( R)- N-(1-(2,4-Dichlorophenyl)-2-(1 H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide)) Derivatives To Target Fungal Infections: Synthesis, Biological Evaluation, and Crystallographic Analysis.
Authors: Friggeri, L. / Hargrove, T.Y. / Wawrzak, Z. / Blobaum, A.L. / Rachakonda, G. / Lindsley, C.W. / Villalta, F. / Nes, W.D. / Botta, M. / Guengerich, F.P. / Lepesheva, G.I.
History
DepositionMar 16, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 27, 2018Provider: repository / Type: Initial release
Revision 1.1Jul 25, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.2Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _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_asym_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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 14-alpha sterol demethylase Cyp51B
B: 14-alpha sterol demethylase Cyp51B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)110,7416
Polymers108,2682
Non-polymers2,4744
Water1,910106
1
A: 14-alpha sterol demethylase Cyp51B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,3713
Polymers54,1341
Non-polymers1,2372
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: 14-alpha sterol demethylase Cyp51B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,3713
Polymers54,1341
Non-polymers1,2372
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)108.438, 108.438, 90.999
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number144
Space group name H-MP31

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Components

#1: Protein 14-alpha sterol demethylase Cyp51B


Mass: 54133.848 Da / Num. of mol.: 2 / Mutation: E51T
Source method: isolated from a genetically manipulated source
Details: UNP residues 51-518 / Source: (gene. exp.) Aspergillus fumigatus (mold) / Strain: ATCC MYA-4609 / Af293 / CBS 101355 / FGSC A1100 / Gene: AFUA_7G03740 / Plasmid: pCW / Production host: Escherichia coli (E. coli) / Strain (production host): HMS174 / References: UniProt: E9QY26, sterol 14alpha-demethylase
#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-LFV / N-[(1R)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl]-4-{5-[2-fluoro-4-(2,2,2-trifluoroethoxy)phenyl]-1,3,4-oxadiazol-2-yl}benzamide


Mass: 620.382 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C28H19Cl2F4N5O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 106 / Source method: isolated from a natural source / Formula: H2O

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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: 2.81 Å3/Da / Density % sol: 56.23 %
Crystal growTemperature: 279 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: 0.2 M lithium acetate, pH 7.4, 19% w/v PEG3350, 5 mM cyclohexylpentanoyl-N-hydroxyethylglucamide

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.97872 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Feb 2, 2018 / Details: Be lenses
RadiationMonochromator: diamond(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 2.38→93.91 Å / Num. obs: 44263 / % possible obs: 96.9 % / Redundancy: 4.9 % / Biso Wilson estimate: 30.1 Å2 / Rmerge(I) obs: 0.039 / Net I/σ(I): 27.1
Reflection shellResolution: 2.38→2.42 Å / Redundancy: 4.9 % / Rmerge(I) obs: 0.698 / Mean I/σ(I) obs: 1.7 / % possible all: 64.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
HKL-2000data reduction
HKL-2000data scaling
PHASER2.7.17phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4UYM

4uym


Resolution: 2.38→30 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.922 / SU B: 7.35 / SU ML: 0.17 / Cross valid method: THROUGHOUT / ESU R: 0.402 / ESU R Free: 0.231 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23 2282 4.9 %RANDOM
Rwork0.2154 ---
obs0.2162 44263 96.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 40.37 Å2
Baniso -1Baniso -2Baniso -3
1--0.05 Å2-0.02 Å20 Å2
2---0.05 Å20 Å2
3---0.16 Å2
Refinement stepCycle: LAST / Resolution: 2.38→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7486 0 170 106 7762
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0010.0197880
X-RAY DIFFRACTIONr_bond_other_d00.027198
X-RAY DIFFRACTIONr_angle_refined_deg1.1181.98710730
X-RAY DIFFRACTIONr_angle_other_deg0.7243.00116688
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.495936
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.93323.237346
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.19151288
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.9891550
X-RAY DIFFRACTIONr_chiral_restr0.0680.21144
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0218710
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021696
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_it4.343.8853750
X-RAY DIFFRACTIONr_mcbond_other4.3363.8843749
X-RAY DIFFRACTIONr_mcangle_it6.6115.824684
X-RAY DIFFRACTIONr_mcangle_other6.6115.8214685
X-RAY DIFFRACTIONr_scbond_it4.8044.2564130
X-RAY DIFFRACTIONr_scbond_other4.8044.2574131
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other7.1886.2086047
X-RAY DIFFRACTIONr_long_range_B_refined11.19146.5829337
X-RAY DIFFRACTIONr_long_range_B_other11.19146.5789336
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.38→2.44 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.267 157 -
Rwork0.289 2152 -
obs--64.88 %

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