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- PDB-4uhl: HUMAN STEROL 14-ALPHA DEMETHYLASE (CYP51) IN COMPLEX WITH VFV IN ... -

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Basic information

Entry
Database: PDB / ID: 4uhl
TitleHUMAN STEROL 14-ALPHA DEMETHYLASE (CYP51) IN COMPLEX WITH VFV IN P1 SPACE GROUP
ComponentsSTEROL 14-ALPHA DEMETHYLASE
KeywordsOXIDOREDUCTASE / CYTOCHROME P450 / CYP51 / MONOOXYGENASE / STEROL BIOSYNTHESIS / EUKARYOTIC MEMBRANES / CYTOCHROME P450 FOLD / ENDOPLASMIC RETICULUM
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 / 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-VFV / Lanosterol 14-alpha demethylase
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsHargrove, T.Y. / Wawrzak, Z. / I Lepesheva, G.
CitationJournal: J.Lipid Res. / Year: 2016
Title: Human Sterol 14Alpha-Demethylase (Cyp51) as a Target for Anticancer Chemotherapy: Towards Structure-Aided Drug Design.
Authors: Hargrove, T.Y. / Friggeri, L. / Wawrzak, Z. / Sivakumaran, S. / Yazlovitskaya, E.M. / Hiebert, S.W. / Guengerich, F.P. / Waterman, M.R. / Lepesheva, G.I.
History
DepositionMar 24, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 15, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 29, 2016Group: Database references
Revision 1.2Aug 10, 2016Group: Database references
Revision 1.3Jan 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
B: STEROL 14-ALPHA DEMETHYLASE
C: STEROL 14-ALPHA DEMETHYLASE
D: STEROL 14-ALPHA DEMETHYLASE
E: STEROL 14-ALPHA DEMETHYLASE
F: STEROL 14-ALPHA DEMETHYLASE
G: STEROL 14-ALPHA DEMETHYLASE
H: STEROL 14-ALPHA DEMETHYLASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)422,11332
Polymers408,4208
Non-polymers13,69324
Water16,718928
1
A: STEROL 14-ALPHA DEMETHYLASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,7644
Polymers51,0531
Non-polymers1,7123
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: STEROL 14-ALPHA DEMETHYLASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,7644
Polymers51,0531
Non-polymers1,7123
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: STEROL 14-ALPHA DEMETHYLASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,7644
Polymers51,0531
Non-polymers1,7123
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: STEROL 14-ALPHA DEMETHYLASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,7644
Polymers51,0531
Non-polymers1,7123
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
5
E: STEROL 14-ALPHA DEMETHYLASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,7644
Polymers51,0531
Non-polymers1,7123
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
6
F: STEROL 14-ALPHA DEMETHYLASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,7644
Polymers51,0531
Non-polymers1,7123
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
7
G: STEROL 14-ALPHA DEMETHYLASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,7644
Polymers51,0531
Non-polymers1,7123
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
8
H: STEROL 14-ALPHA DEMETHYLASE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,7644
Polymers51,0531
Non-polymers1,7123
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)111.210, 111.500, 118.480
Angle α, β, γ (deg.)64.09, 75.07, 62.42
Int Tables number1
Space group name H-MP1

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Components

#1: Protein
STEROL 14-ALPHA DEMETHYLASE / LDM / CYPLI / CYTOCHROME P450 51A1 / CYTOCHROME P450-14DM / CYTOCHROME P45014DM / CYTOCHROME P450LI ...LDM / CYPLI / CYTOCHROME P450 51A1 / CYTOCHROME P450-14DM / CYTOCHROME P45014DM / CYTOCHROME P450LI / LANOSTEROL 14-ALPHA DEMETHYLASE / STEROL 14ALPHA DEMETHYLASE


Mass: 51052.539 Da / Num. of mol.: 8 / Fragment: UNP RESIDUES 61-503
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / 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.: 8 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical
ChemComp-VFV / N-[(1R)-1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl]-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide


Mass: 547.554 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: C32H23F2N5O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 928 / 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: 2.7 Å3/Da / Density % sol: 53.7 % / 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: 0.9787
DetectorType: MARRESEARCH / Detector: CCD / Date: Feb 6, 2015 / Details: BE LENSES DIAMOND LAUE
RadiationMonochromator: DIAMOND / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 2.5→54.3 Å / Num. obs: 154245 / % possible obs: 98.5 % / Observed criterion σ(I): 2 / Redundancy: 3.9 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 14
Reflection shellResolution: 2.5→2.56 Å / Redundancy: 4 % / Rmerge(I) obs: 0.62 / Mean I/σ(I) obs: 2 / % possible all: 97.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0107refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERMRphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 4UHI

4uhi


Resolution: 2.5→54.27 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.936 / SU B: 11.2 / SU ML: 0.239 / Cross valid method: THROUGHOUT / ESU R: 0.55 / ESU R Free: 0.277 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2371 7786 5.3 %RANDOM
Rwork0.19013 ---
obs0.19249 146458 98.48 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 64.354 Å2
Baniso -1Baniso -2Baniso -3
1-0.14 Å2-1.14 Å22.57 Å2
2---1.76 Å2-1.69 Å2
3---0.14 Å2
Refinement stepCycle: LAST / Resolution: 2.5→54.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms28704 0 1000 928 30632
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.0230584
X-RAY DIFFRACTIONr_bond_other_d0.0050.0228760
X-RAY DIFFRACTIONr_angle_refined_deg0.8732.0141568
X-RAY DIFFRACTIONr_angle_other_deg0.5723.00466152
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.73753552
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.25623.4711360
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.83155120
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.15315200
X-RAY DIFFRACTIONr_chiral_restr0.0530.24344
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.02134240
X-RAY DIFFRACTIONr_gen_planes_other0.0040.027384
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_it4.4186.26714232
X-RAY DIFFRACTIONr_mcbond_other4.4186.26614231
X-RAY DIFFRACTIONr_mcangle_it6.2189.417776
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it4.9446.54116352
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: 2.5→2.565 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.346 573 -
Rwork0.287 10731 -
obs--97.72 %

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