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- PDB-9nnj: Crystal structure of CYP46A1 with 3-chloro-N-[(3M)-3-(1,3-oxazol-... -

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Basic information

Entry
Database: PDB / ID: 9nnj
TitleCrystal structure of CYP46A1 with 3-chloro-N-[(3M)-3-(1,3-oxazol-5-yl)phenyl]-N-(propan-2-yl)benzene-1-sulfonamide (compound 2)
ComponentsCholesterol 24-hydroxylase
KeywordsHYDROLASE/INHIBITOR / Inhibitor / Complex / CH24H / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


cholesterol 24-hydroxylase / cholesterol 24-hydroxylase activity / protein localization to membrane raft / testosterone 16-beta-hydroxylase activity / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / bile acid biosynthetic process / progesterone metabolic process / testosterone 6-beta-hydroxylase activity / sterol metabolic process / steroid hydroxylase activity ...cholesterol 24-hydroxylase / cholesterol 24-hydroxylase activity / protein localization to membrane raft / testosterone 16-beta-hydroxylase activity / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / bile acid biosynthetic process / progesterone metabolic process / testosterone 6-beta-hydroxylase activity / sterol metabolic process / steroid hydroxylase activity / cholesterol catabolic process / regulation of long-term synaptic potentiation / Endogenous sterols / xenobiotic metabolic process / nervous system development / presynapse / postsynapse / iron ion binding / heme binding / dendrite / endoplasmic reticulum membrane / endoplasmic reticulum
Similarity search - Function
Cholesterol 24-hydroxylase / Cytochrome P450, E-class, group I / 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 / Cholesterol 24-hydroxylase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.29 Å
AuthorsYano, J. / Skene, R.J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem. / Year: 2025
Title: Design and identification of brain-penetrant, potent, and selective 1,3-oxazole-based cholesterol 24-hydroxylase (CH24H) inhibitors.
Authors: Ito, Y. / Kimura, E. / Nomura, I. / Watanabe, E. / Yano, J. / Skene, R. / Miyamoto, M. / Ishii, T. / Nishi, T. / Koike, T.
History
DepositionMar 5, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 23, 2025Provider: repository / Type: Initial release

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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)55,4904
Polymers54,4351
Non-polymers1,0553
Water2,594144
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2280 Å2
ΔGint-17 kcal/mol
Surface area18580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.104, 63.626, 123.138
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 54434.723 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CYP46A1, CYP46 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9Y6A2, cholesterol 24-hydroxylase
#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-A1BZB / 3-chloro-N-[(3M)-3-(1,3-oxazol-5-yl)phenyl]-N-(propan-2-yl)benzene-1-sulfonamide


Mass: 376.857 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H17ClN2O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 144 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.09 Å3/Da / Density % sol: 41.17 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 18.5% PEG3350, 0.4 M calcium chloride

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.976 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Feb 24, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.29→50 Å / Num. obs: 20806 / % possible obs: 98.2 % / Redundancy: 4.7 % / Rmerge(I) obs: 0.165 / Χ2: 1.016 / Net I/σ(I): 5
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
2.3-2.343.10.5929100.938187.7
2.34-2.383.40.5799490.927192
2.38-2.433.70.5489931.014194.9
2.43-2.4840.50510160.994198.9
2.48-2.534.20.56810661.049199.9
2.53-2.594.70.50410230.9951100
2.59-2.664.90.54110541.0651100
2.66-2.735.10.43310191.0071100
2.73-2.815.20.40110501.059199.9
2.81-2.95.20.33710601.042199.7
2.9-35.20.30110261.021199.8
3-3.125.10.2510591.041199.7
3.12-3.265.20.19810501.017199.8
3.26-3.445.20.15310551.011199.7
3.44-3.655.10.12510521.001199.5
3.65-3.935.10.1110591.027199.5
3.93-4.3350.09910671199.2
4.33-4.9550.08910671.023198.9
4.95-6.244.90.08910851.008198.4
6.24-504.80.0611460.995196.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0419refinement
HKL-2000data scaling
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.29→35.2 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.924 / SU B: 17.124 / SU ML: 0.2 / Cross valid method: THROUGHOUT / ESU R: 0.397 / ESU R Free: 0.236 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.23195 1051 5.1 %RANDOM
Rwork0.19333 ---
obs0.19534 19722 97.99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.301 Å2
Baniso -1Baniso -2Baniso -3
1--1.35 Å2-0 Å2-0 Å2
2--0.41 Å2-0 Å2
3---0.94 Å2
Refinement stepCycle: 1 / Resolution: 2.29→35.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3502 0 72 144 3718
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0123655
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.1621.6914946
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6445431
X-RAY DIFFRACTIONr_dihedral_angle_2_deg4.384535
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.69510651
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0960.2529
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022763
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_it1.1912.0991733
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.063.7622161
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.9132.3831922
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined5.56724.495638
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: 2.291→2.351 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.311 67 -
Rwork0.275 1253 -
obs--85.11 %
Refinement TLS params.Method: refined / Origin x: 13.9198 Å / Origin y: -4.6325 Å / Origin z: -18.7757 Å
111213212223313233
T0.044 Å20.0031 Å2-0.0005 Å2-0.013 Å20.0005 Å2--0.0146 Å2
L0.5128 °2-0.0119 °20.0059 °2-1.7582 °2-0.0578 °2--1.0201 °2
S0.0036 Å °0.0801 Å °-0.0055 Å °-0.1001 Å °-0.0101 Å °-0.0041 Å °-0.0181 Å °0.0151 Å °0.0065 Å °

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