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

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Basic information

Entry
Database: PDB / ID: 4uhi
TitleHUMAN STEROL 14-ALPHA DEMETHYLASE (CYP51) IN COMPLEX WITH VFV IN C121 SPACE GROUP
ComponentsSTEROL 14-ALPHA DEMETHYLASE
KeywordsOXIDOREDUCTASE / 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: 2.04 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 8, 2016Provider: repository / Type: Initial release
Revision 1.1Jun 29, 2016Group: Database references
Revision 1.2Aug 10, 2016Group: Database references
Revision 1.3Jun 20, 2018Group: Advisory / Data collection / Derived calculations
Category: pdbx_validate_symm_contact / struct_conn / struct_conn_type
Revision 1.4May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_conn / 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_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 / _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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)209,85916
Polymers203,0134
Non-polymers6,84612
Water11,782654
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area11340 Å2
ΔGint-141.8 kcal/mol
Surface area68400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)168.663, 145.869, 115.987
Angle α, β, γ (deg.)90.00, 127.15, 90.00
Int Tables number5
Space group name H-MC121

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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: 50753.156 Da / Num. of mol.: 4 / 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.: 4 / 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.: 8 / Source method: obtained synthetically / Formula: C32H23F2N5O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 654 / 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: 2.5 Å3/Da / Density % sol: 52.4 % / 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 5, 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: 2.04→98.9 Å / Num. obs: 140942 / % possible obs: 98.8 % / Observed criterion σ(I): 2 / Redundancy: 4.6 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 13
Reflection shellResolution: 2.04→2.28 Å / Redundancy: 4.7 % / Rmerge(I) obs: 0.49 / Mean I/σ(I) obs: 3 / % possible all: 98.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0107refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERMRphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.04→50.01 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.937 / SU B: 5.417 / SU ML: 0.141 / Cross valid method: THROUGHOUT / ESU R: 0.207 / ESU R Free: 0.164 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.23277 7049 5 %RANDOM
Rwork0.21488 ---
obs0.21578 133884 98.81 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 40.568 Å2
Baniso -1Baniso -2Baniso -3
1-2.69 Å20 Å2-0.31 Å2
2---0.24 Å20 Å2
3----0.92 Å2
Refinement stepCycle: LAST / Resolution: 2.04→50.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms14268 0 500 654 15422
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0215208
X-RAY DIFFRACTIONr_bond_other_d0.0010.0214272
X-RAY DIFFRACTIONr_angle_refined_deg0.9812.00920672
X-RAY DIFFRACTIONr_angle_other_deg0.63.00432820
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.59451764
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.97523.471680
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.117152536
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.51515100
X-RAY DIFFRACTIONr_chiral_restr0.0610.22160
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.02117032
X-RAY DIFFRACTIONr_gen_planes_other0.0020.023684
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_it3.7663.7937068
X-RAY DIFFRACTIONr_mcbond_other3.7653.7927067
X-RAY DIFFRACTIONr_mcangle_it5.085.6798828
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it4.4074.1638139
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: 2.036→2.089 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.324 570 -
Rwork0.323 9812 -
obs--98.61 %

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