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- PDB-8vk6: 14alpha-demethylase (CYP51) with amide-linked long arm extension ... -

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Basic information

Entry
Database: PDB / ID: 8vk6
Title14alpha-demethylase (CYP51) with amide-linked long arm extension antifungal azole inhibitor
ComponentsLanosterol 14-alpha demethylase
KeywordsOXIDOREDUCTASE/INHIBITOR / amide-linked azole inhibitor / CYP51 / OXIDOREDUCTASE-INHIBITOR complex
Function / homology
Function and homology information


sterol 14alpha-demethylase / ergosterol biosynthetic process / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen / methyltransferase activity / monooxygenase activity / methylation / iron ion binding / heme binding / 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 / sterol 14alpha-demethylase
Similarity search - Component
Biological speciesSaccharomyces cerevisiae YJM789 (yeast)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.89 Å
AuthorsTyndall, J.D.A. / Monk, B.C. / Simons, C.
Funding supportEuropean Union, New Zealand, 2items
OrganizationGrant numberCountry
European Regional Development FundEuropean Union
Health Research Council (HRC)19/397 New Zealand
CitationJournal: J.Med.Chem. / Year: 2025
Title: Exploring Long Arm Amide-Linked Side Chains in the Design of Antifungal Azole Inhibitors of Sterol 14 alpha-Demethylase (CYP51).
Authors: Alsulaimany, M. / Keniya, M.V. / Alanazi, R.S. / N Ruma, Y. / Hughes, C.S. / Jones, A.T. / Tyndall, J.D.A. / Parker, J.E. / Monk, B.C. / Simons, C.
History
DepositionJan 8, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 15, 2025Provider: repository / Type: Initial release
Revision 1.1Jul 30, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Lanosterol 14-alpha demethylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,7695
Polymers61,8851
Non-polymers1,8844
Water2,468137
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3340 Å2
ΔGint-35 kcal/mol
Surface area23850 Å2
MethodPISA
Unit cell
Length a, b, c (Å)76.686, 65.537, 80.962
Angle α, β, γ (deg.)90.000, 98.500, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

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Protein / Sugars , 2 types, 2 molecules A

#1: Protein Lanosterol 14-alpha demethylase


Mass: 61885.215 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Saccharomyces cerevisiae YJM789 (yeast)
Strain: YJM789 / Gene: ERG11, SCY_2394 / Production host: Saccharomyces cerevisiae (brewer's yeast) / Strain (production host): AD2DELTA / References: UniProt: A6ZSR0
#5: Sugar ChemComp-LMT / DODECYL-BETA-D-MALTOSIDE


Type: D-saccharide / Mass: 510.615 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H46O11 / Comment: detergent*YM

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Non-polymers , 4 types, 140 molecules

#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-A1AB6 / N-[(2S)-2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl]-4'-(trifluoromethoxy)[1,1'-biphenyl]-4-carboxamide


Mass: 518.435 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H19F5N4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-1PE / PENTAETHYLENE GLYCOL / PEG400


Mass: 238.278 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H22O6 / Comment: precipitant*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 137 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.25 Å3/Da / Density % sol: 62.17 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 9.5 / Details: 44% PEG400, 0.1 M glycine, pH 9.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.954 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Apr 28, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.954 Å / Relative weight: 1
ReflectionResolution: 1.89→44.11 Å / Num. obs: 61571 / % possible obs: 97 % / Redundancy: 3.6 % / Biso Wilson estimate: 38.62 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.051 / Rpim(I) all: 0.035 / Net I/σ(I): 7
Reflection shellResolution: 1.89→1.93 Å / Rmerge(I) obs: 1.233 / Mean I/σ(I) obs: 0.6 / Num. unique obs: 3811 / CC1/2: 0.496 / Rpim(I) all: 0.924 / % possible all: 92.9

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
Aimlessdata scaling
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4LXJ

4lxj


Resolution: 1.89→44.11 Å / SU ML: 0.2766 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 24.9793
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2255 2004 3.26 %
Rwork0.1957 59497 -
obs0.1966 61501 96.62 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 46.09 Å2
Refinement stepCycle: LAST / Resolution: 1.89→44.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4256 0 131 137 4524
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00754523
X-RAY DIFFRACTIONf_angle_d0.86116139
X-RAY DIFFRACTIONf_chiral_restr0.0509650
X-RAY DIFFRACTIONf_plane_restr0.0066794
X-RAY DIFFRACTIONf_dihedral_angle_d14.36261690
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.89-1.940.35731320.36514067X-RAY DIFFRACTION92.65
1.94-1.990.31771480.31274157X-RAY DIFFRACTION95.54
1.99-2.050.3471480.28714128X-RAY DIFFRACTION94.92
2.05-2.120.30861290.25464195X-RAY DIFFRACTION95.52
2.12-2.190.26931450.23954194X-RAY DIFFRACTION94.76
2.19-2.280.21961350.22524194X-RAY DIFFRACTION97
2.28-2.380.24071470.19814247X-RAY DIFFRACTION96.85
2.38-2.510.21121460.17784244X-RAY DIFFRACTION97.02
2.51-2.670.21661510.17314309X-RAY DIFFRACTION98.02
2.67-2.870.21441410.18154310X-RAY DIFFRACTION97.65
2.87-3.160.21191450.18484299X-RAY DIFFRACTION98.08
3.16-3.620.20191390.18654361X-RAY DIFFRACTION98.51
3.62-4.560.21351490.17364332X-RAY DIFFRACTION97.56
4.56-44.110.22291490.19494460X-RAY DIFFRACTION98.59

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