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- PDB-8ss0: Human sterol 14 alpha-demethylase (CYP51) in complex with the rea... -

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Basic information

Entry
Database: PDB / ID: 8ss0
TitleHuman sterol 14 alpha-demethylase (CYP51) in complex with the reaction intermediate 14 alpha-aldehyde dihydrolanosterol
ComponentsLanosterol 14-alpha demethylase
KeywordsOXIDOREDUCTASE / MONOOXYGENASE / CYTOCHROME P450 / CYP51 / ENDOPLASMIC RETICULUM / STEROL BIOSYNTHESIS
Function / homology
Function and homology information


cholesterol biosynthetic process via 24,25-dihydrolanosterol / sterol 14-demethylase activity / sterol 14alpha-demethylase / negative regulation of amyloid-beta clearance / sterol metabolic process / Cholesterol biosynthesis / EGR2 and SOX10-mediated initiation of Schwann cell myelination / steroid biosynthetic process / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen / cholesterol biosynthetic process ...cholesterol biosynthetic process via 24,25-dihydrolanosterol / sterol 14-demethylase activity / sterol 14alpha-demethylase / negative regulation of amyloid-beta clearance / sterol metabolic process / Cholesterol biosynthesis / EGR2 and SOX10-mediated initiation of Schwann cell myelination / steroid biosynthetic process / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen / cholesterol biosynthetic process / negative regulation of protein secretion / Endogenous sterols / Activation of gene expression by SREBF (SREBP) / negative regulation of protein catabolic process / oxidoreductase activity / iron ion binding / heme binding / endoplasmic reticulum membrane / 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-WQR / Lanosterol 14-alpha demethylase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsHargrove, T.Y. / Wawrzak, Z. / Guengerich, F.P. / Lepesheva, G.I.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM067871 United States
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2024
Title: Oxygen-18 Labeling Reveals a Mixed Fe-O Mechanism in the Last Step of Cytochrome P450 51 Sterol 14 alpha-Demethylation.
Authors: McCarty, K.D. / Tateishi, Y. / Hargrove, T.Y. / Lepesheva, G.I. / Guengerich, F.P.
History
DepositionMay 8, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 17, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Database references / Category: citation
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Mar 6, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Lanosterol 14-alpha demethylase
B: Lanosterol 14-alpha demethylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)106,8336
Polymers104,7182
Non-polymers2,1144
Water1,928107
1
A: Lanosterol 14-alpha demethylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,4163
Polymers52,3591
Non-polymers1,0572
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Lanosterol 14-alpha demethylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,4163
Polymers52,3591
Non-polymers1,0572
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)145.803, 145.803, 261.161
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number180
Space group name H-MP6222
Components on special symmetry positions
IDModelComponents
11B-761-

HOH

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Components

#1: Protein Lanosterol 14-alpha demethylase / LDM / CYPLI / Cytochrome P450 51A1 / CYP51A1 / Cytochrome P450-14DM / Cytochrome P45014DM / ...LDM / CYPLI / Cytochrome P450 51A1 / CYP51A1 / Cytochrome P450-14DM / Cytochrome P45014DM / Cytochrome P450LI / Sterol 14-alpha demethylase


Mass: 52359.113 Da / Num. of mol.: 2 / Mutation: D231A, H314A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP51A1, CYP51 / Plasmid: pCW / Production host: Escherichia coli (E. coli) / Strain (production host): HMS174 / References: UniProt: Q16850, 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-WQR / 3beta-hydroxy-10alpha,13alpha-lanosta-8,24-dien-30-al


Mass: 440.701 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H48O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 107 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.83 Å3/Da / Density % sol: 67.85 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop / pH: 7.4
Details: CALCIUM ACATATE, PEG 4000, ANAPOE 80, 14 ALPHA ALDEHYDE DERIVATIVE OD DIHYDROLANOSTEROL

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-D / Wavelength: 1.12713 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Apr 6, 2023 / Details: Focusing Mirrors
RadiationMonochromator: Si (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.12713 Å / Relative weight: 1
ReflectionResolution: 2.25→19.89 Å / Num. obs: 36891 / % possible obs: 94.9 % / Redundancy: 4.4 % / Biso Wilson estimate: 33 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.085 / Rrim(I) all: 0.097 / Net I/σ(I): 5.8
Reflection shellResolution: 2.25→2.5 Å / Redundancy: 3.6 % / Rmerge(I) obs: 0.602 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 1845 / CC1/2: 0.848 / Rpim(I) all: 0.356 / Rrim(I) all: 0.705 / % possible all: 83.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0405refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6uez

6uez


Resolution: 2.25→19.89 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.933 / SU B: 6.623 / SU ML: 0.16 / Cross valid method: THROUGHOUT / ESU R: 0.743 / ESU R Free: 0.309 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.249 1827 5 %RANDOM
Rwork0.219 ---
obs0.219 35064 47.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 37.13 Å2
Baniso -1Baniso -2Baniso -3
1-0.02 Å20.01 Å20 Å2
2--0.02 Å20 Å2
3----0.06 Å2
Refinement stepCycle: LAST / Resolution: 2.25→19.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7122 0 150 107 7379
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0127492
X-RAY DIFFRACTIONr_bond_other_d0.0020.0167142
X-RAY DIFFRACTIONr_angle_refined_deg1.4461.68810195
X-RAY DIFFRACTIONr_angle_other_deg0.511.60516462
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.2525885
X-RAY DIFFRACTIONr_dihedral_angle_2_deg7.854548
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.354101275
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0640.21094
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.028603
X-RAY DIFFRACTIONr_gen_planes_other0.0030.021753
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_it3.1823.5583549
X-RAY DIFFRACTIONr_mcbond_other3.183.5583549
X-RAY DIFFRACTIONr_mcangle_it5.1036.3834431
X-RAY DIFFRACTIONr_mcangle_other5.1036.3844432
X-RAY DIFFRACTIONr_scbond_it3.8373.8833943
X-RAY DIFFRACTIONr_scbond_other3.8373.8823944
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.4116.9265765
X-RAY DIFFRACTIONr_long_range_B_refined9.27433.398624
X-RAY DIFFRACTIONr_long_range_B_other9.27533.398621
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.26→2.31 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.361 9 -
Rwork0.366 169 -
obs--3.19 %

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