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- PDB-9nno: Crystal structure of CYP46A1 with N-[6-(1,3-oxazol-5-yl)-4-(trifl... -

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Basic information

Entry
Database: PDB / ID: 9nno
TitleCrystal structure of CYP46A1 with N-[6-(1,3-oxazol-5-yl)-4-(trifluoromethyl)pyridin-2-yl]cyclopropanecarboxamide (compound 4l)
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: 1.8 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)55,4735
Polymers54,4351
Non-polymers1,0384
Water4,918273
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1650 Å2
ΔGint-16 kcal/mol
Surface area18950 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.294, 63.511, 123.595
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-A1BY9 / N-[6-(1,3-oxazol-5-yl)-4-(trifluoromethyl)pyridin-2-yl]cyclopropanecarboxamide


Mass: 297.233 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H10F3N3O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 273 / 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: 2.1 Å3/Da / Density % sol: 41.47 %
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 9, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 43035 / % possible obs: 99.6 % / Redundancy: 6.6 % / Rmerge(I) obs: 0.098 / Χ2: 1.005 / Net I/σ(I): 9.2 / Num. measured all: 283935
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
1.8-1.836.10.94621050.946198.5
1.83-1.866.40.83421130.987199.2
1.86-1.96.50.72220811.004199.6
1.9-1.946.50.57121260.998199
1.94-1.986.60.50821241.037199.5
1.98-2.036.60.42120981.039199.5
2.03-2.086.60.33521201.03199.2
2.08-2.136.60.30221321.024199.5
2.13-2.26.70.23821240.997199.5
2.2-2.276.60.21321421.015199.6
2.27-2.356.70.18421461.018199.9
2.35-2.446.70.14621350.995199.6
2.44-2.556.70.13521490.998199.9
2.55-2.696.80.1221571.003199.9
2.69-2.866.90.09921501.017199.9
2.86-3.086.80.08821811.0081100
3.08-3.396.70.07221740.9911100
3.39-3.886.60.05821961.011100
3.88-4.886.50.03922310.983199.8
4.88-506.40.03423510.999199.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0419refinement
HKL-2000data scaling
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→35.27 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.946 / SU B: 5.857 / SU ML: 0.089 / Cross valid method: THROUGHOUT / ESU R: 0.136 / ESU R Free: 0.121 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.21475 2135 5 %RANDOM
Rwork0.18932 ---
obs0.19061 40844 99.36 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 27.108 Å2
Baniso -1Baniso -2Baniso -3
1--1.06 Å20 Å2-0 Å2
2--1.08 Å20 Å2
3----0.01 Å2
Refinement stepCycle: 1 / Resolution: 1.8→35.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3491 0 72 273 3836
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0123674
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0491.6894983
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4465444
X-RAY DIFFRACTIONr_dihedral_angle_2_deg3.19535
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.06610651
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0830.2539
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022779
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_it0.9911.6551749
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.7532.9612184
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.3621.8521925
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined5.00519.735703
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: 1.801→1.848 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.308 139 -
Rwork0.272 2881 -
obs--95.66 %
Refinement TLS params.Method: refined / Origin x: 13.8251 Å / Origin y: -4.7419 Å / Origin z: -18.7258 Å
111213212223313233
T0.0131 Å20.0052 Å20.0022 Å2-0.0129 Å20.0027 Å2--0.0269 Å2
L0.4812 °20.0249 °2-0.092 °2-1.7438 °2-0.062 °2--0.9098 °2
S0.0185 Å °0.0642 Å °0.0072 Å °-0.1316 Å °-0.015 Å °-0.0179 Å °-0.0366 Å °-0.0021 Å °-0.0035 Å °

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