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- PDB-3ld6: Crystal structure of human lanosterol 14alpha-demethylase (CYP51)... -

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Basic information

Entry
Database: PDB / ID: 3ld6
TitleCrystal structure of human lanosterol 14alpha-demethylase (CYP51) in complex with ketoconazole
ComponentsLanosterol 14-alpha demethylase
KeywordsOXIDOREDUCTASE / cytochrome P450 / sterol 14alpha-demethylase / ketoconazole / Structural Genomics / Structural Genomics Consortium / SGC / Alternative splicing / Cholesterol biosynthesis / Endoplasmic reticulum / Heme / Iron / Lipid synthesis / Membrane / Metal-binding / Microsome / Monooxygenase / NADP / Polymorphism / Steroid biosynthesis / Sterol biosynthesis / Transmembrane
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
beta-cyclodextrin / PROTOPORPHYRIN IX CONTAINING FE / Chem-KKK / Lanosterol 14-alpha demethylase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsStrushkevich, N. / Tempel, W. / MacKenzie, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Weigelt, J. / Park, H. / Structural Genomics Consortium (SGC)
CitationJournal: J.Mol.Biol. / Year: 2010
Title: Structural basis of human CYP51 inhibition by antifungal azoles.
Authors: Strushkevich, N. / Usanov, S.A. / Park, H.W.
History
DepositionJan 12, 2010Deposition site: RCSB / Processing site: RCSB
SupersessionFeb 2, 2010ID: 3I3K
Revision 1.0Feb 2, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jan 24, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.3Apr 18, 2018Group: Data collection / Category: diffrn_detector / Item: _diffrn_detector.detector
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations / Non-polymer description / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / entity_name_com / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_molecule_features / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_struct_conn_angle / struct_asym / struct_conn / struct_conn_type / struct_ref_seq_dif / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.pdbx_synonyms / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _entity.src_method / _entity.type / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_asym.entity_id / _struct_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)110,1418
Polymers105,5392
Non-polymers4,6026
Water68538
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Lanosterol 14-alpha demethylase
hetero molecules

B: Lanosterol 14-alpha demethylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)110,1418
Polymers105,5392
Non-polymers4,6026
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555y+1/2,-x+1/2,z1
Buried area7670 Å2
ΔGint-115 kcal/mol
Surface area37360 Å2
MethodPISA
Unit cell
Length a, b, c (Å)145.726, 145.726, 110.341
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number90
Space group name H-MP4212

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Components

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


Mass: 52769.465 Da / Num. of mol.: 2 / Fragment: UNP residues 54-502
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP51, CYP51A1 / Plasmid: pCW / Production host: Escherichia coli (E. coli) / Strain (production host): JM109 / References: UniProt: Q16850, sterol 14alpha-demethylase
#2: Polysaccharide Cycloheptakis-(1-4)-(alpha-D-glucopyranose) / beta-cyclodextrin


Type: oligosaccharide, Oligosaccharide / Class: Drug delivery / Mass: 1153.001 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: cyclic oligosaccharide / References: beta-cyclodextrin
DescriptorTypeProgram
WURCS=2.0/1,7,7/[a2122h-1a_1-5]/1-1-1-1-1-1-1/a1-g4_a4-b1_b4-c1_c4-d1_d4-e1_e4-f1_f4-g1WURCSPDB2Glycan 1.1.0
#3: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#4: Chemical ChemComp-KKK / 1-acetyl-4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazine


Mass: 531.431 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H28Cl2N4O4 / Comment: medication, antifungal*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 38 / 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: 2.78 Å3/Da / Density % sol: 55.68 %
Crystal growTemperature: 291 K / Method: vapor diffusion / pH: 7.5
Details: 2.5M (NH4)2SO4, 0.1M Hepes, pH 7.5, VAPOR DIFFUSION, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 19-ID
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Mar 18, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.8→24.39 Å / Num. all: 28290 / Num. obs: 27984 / % possible obs: 98.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 12.7 % / Rmerge(I) obs: 0.066 / Rsym value: 0.091 / Net I/σ(I): 33.4
Reflection shellResolution: 2.8→2.85 Å / Redundancy: 12.7 % / Rmerge(I) obs: 0.507 / Mean I/σ(I) obs: 3.61 / Rsym value: 0.588 / % possible all: 98.9

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Processing

Software
NameVersionClassification
HKL-2000data collection
CCP4MOLREPmodel building
REFMAC5refinement
HKL-2000data reduction
HKL-2000data scaling
CCP4MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 3G1Q

3g1q


Resolution: 2.8→24.29 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.897 / SU B: 14.059 / SU ML: 0.288 / Cross valid method: THROUGHOUT / ESU R Free: 0.408 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27535 1491 5.1 %RANDOM
Rwork0.21196 ---
obs0.21514 27984 98.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 55.488 Å2
Baniso -1Baniso -2Baniso -3
1-0.61 Å20 Å20 Å2
2--0.61 Å20 Å2
3----1.22 Å2
Refinement stepCycle: LAST / Resolution: 2.8→24.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7172 0 312 38 7522
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0227706
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.2272.03710498
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6155887
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.62723.471340
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.86151279
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7341550
X-RAY DIFFRACTIONr_chiral_restr0.0820.21155
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0215738
X-RAY DIFFRACTIONr_gen_planes_other
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_it0.4351.54443
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.84627200
X-RAY DIFFRACTIONr_scbond_it1.11933263
X-RAY DIFFRACTIONr_scangle_it1.9254.53298
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.8→2.872 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.32 115 -
Rwork0.254 1998 -
obs--98.74 %

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