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- PDB-4j14: Crystal Structure of Human Cytochrome P450 CYP46A1 with Posaconaz... -

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Basic information

Entry
Database: PDB / ID: 4j14
TitleCrystal Structure of Human Cytochrome P450 CYP46A1 with Posaconazole Bound
ComponentsCholesterol 24-hydroxylase
KeywordsOXIDOREDUCTASE / enzyme / P450 / posaconazole / endoplasmic reticulum / Cholesterol 24-hydroxylase
Function / homology
Function and homology information


cholesterol 24-hydroxylase / cholesterol 24-hydroxylase activity / protein localization to membrane raft / testosterone 16-beta-hydroxylase activity / bile acid biosynthetic process / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / progesterone metabolic process / sterol metabolic process / steroid hydroxylase activity / cholesterol catabolic process ...cholesterol 24-hydroxylase / cholesterol 24-hydroxylase activity / protein localization to membrane raft / testosterone 16-beta-hydroxylase activity / bile acid biosynthetic process / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / progesterone metabolic process / sterol metabolic process / steroid hydroxylase activity / cholesterol catabolic process / regulation of long-term synaptic potentiation / Endogenous sterols / xenobiotic metabolic process / presynapse / nervous system development / postsynapse / iron ion binding / dendrite / heme binding / endoplasmic reticulum membrane / endoplasmic reticulum
Similarity search - Function
Cholesterol 24-hydroxylase / Cytochrome P450, E-class, group I / 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 / POSACONAZOLE / Cholesterol 24-hydroxylase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsStout, C.D. / Mast, N. / Pikuleva, I.A.
CitationJournal: Mol.Pharmacol. / Year: 2013
Title: Antifungal Azoles: Structural Insights into Undesired Tight Binding to Cholesterol-Metabolizing CYP46A1.
Authors: Mast, N. / Zheng, W. / Stout, C.D. / Pikuleva, I.A.
History
DepositionJan 31, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 15, 2014Provider: repository / Type: Initial release
Revision 1.1Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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.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_conn.pdbx_dist_value / _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_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_ref_seq_dif.details / _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

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Assembly

Deposited unit
A: Cholesterol 24-hydroxylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,5344
Polymers52,1251
Non-polymers1,4093
Water1,47782
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)121.640, 121.640, 143.390
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number98
Space group name H-MI4122

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Components

#1: Protein Cholesterol 24-hydroxylase / CH24H / Cytochrome P450 46A1


Mass: 52125.086 Da / Num. of mol.: 1 / Fragment: UNP residues 51-500
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CP46A_HUMAN, CYP46, CYP46A1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9Y6A2, EC: 1.14.13.98
#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-X2N / POSACONAZOLE


Mass: 700.777 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C37H42F2N8O4 / Comment: medication, antifungal*YM
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 82 / 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: 2.54 Å3/Da / Density % sol: 51.65 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop / pH: 5.8
Details: 15% PEG 8000, 50 mM posaconazole, 50 mM potassium phosphate, 20% glycerol, pH 5.8, VAPOR DIFFUSION, SITTING DROP, temperature 290.K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 1.09717 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 1, 2011 / Details: Rh coated flat mirror
RadiationMonochromator: Side scattering I-beam bent single crystal; asymmetric cut 4.9650 deg.
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.09717 Å / Relative weight: 1
ReflectionResolution: 2.5→92.78 Å / Num. all: 17968 / Num. obs: 17993 / % possible obs: 99.86 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 7.1 % / Biso Wilson estimate: 46.193 Å2 / Rmerge(I) obs: 0.11 / Rsym value: 0.11 / Net I/σ(I): 5.8
Reflection shellResolution: 2.5→2.64 Å / Redundancy: 7.3 % / Rmerge(I) obs: 0.535 / Mean I/σ(I) obs: 0.535 / Num. unique all: 2715 / Rsym value: 0.014 / % possible all: 100

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
PHASERphasing
REFMAC5.5.0110refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ENH

4enh


Resolution: 2.5→92.78 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.913 / SU B: 20.03 / SU ML: 0.192 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.123 / ESU R Free: 0.064 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2626 977 5.2 %RANDOM
Rwork0.21337 ---
obs0.21588 17968 99.86 %-
all-17993 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 39.104 Å2
Baniso -1Baniso -2Baniso -3
1--9.31 Å20 Å20 Å2
2---9.31 Å20 Å2
3---18.62 Å2
Refinement stepCycle: LAST / Resolution: 2.5→92.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3507 0 100 82 3689
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0214125
X-RAY DIFFRACTIONr_angle_refined_deg1.3811.9686318
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1137.5870
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.64223.077169
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.76415655
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.1751535
X-RAY DIFFRACTIONr_chiral_restr0.1150.2537
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0214568
X-RAY DIFFRACTIONr_mcbond_it0.8051.52171
X-RAY DIFFRACTIONr_mcangle_it1.52623504
X-RAY DIFFRACTIONr_scbond_it2.31931519
X-RAY DIFFRACTIONr_scangle_it3.8014.51488
LS refinement shellResolution: 2.5→2.564 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.485 77 -
Rwork0.347 1265 -
obs-1265 98.53 %
Refinement TLS params.Method: refined / Origin x: 2.3867 Å / Origin y: -35.113 Å / Origin z: -11.4476 Å
111213212223313233
T0.0345 Å2-0.0176 Å2-0.0109 Å2-0.016 Å20.0158 Å2--0.0247 Å2
L0.7126 °20.3507 °2-0.0808 °2-1.559 °2-0.2534 °2--0.3336 °2
S0.0403 Å °0.0074 Å °0.042 Å °-0.0603 Å °0.0444 Å °0.1037 Å °0.0216 Å °-0.0447 Å °-0.0847 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A56 - 491
2X-RAY DIFFRACTION1A601 - 602

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