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- PDB-9nne: Crystal structure of CYP46A1 with (morpholin-4-yl)[(4R,8M)-8-(1,3... -

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Basic information

Entry
Database: PDB / ID: 9nne
TitleCrystal structure of CYP46A1 with (morpholin-4-yl)[(4R,8M)-8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methanone (compound 2h)
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: 1.95 Å
AuthorsYano, J. / Skene, R.J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem. / Year: 2025
Title: Structure-based design of a novel series of cholesterol 24-hydroxylase (CH24H) inhibitors bearing 1,3-oxazole as a heme-iron binding group.
Authors: Ito, Y. / Hasui, T. / Kimura, E. / Nomura, I. / Fukuda, H. / Ando, H.K. / Watanabe, E. / Yano, J. / Skene, R. / Miyamoto, M. / Ishii, T. / Nishi, T. / Koike, T.
History
DepositionMar 5, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 2, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cholesterol 24-hydroxylase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,4183
Polymers54,4351
Non-polymers9832
Water6,269348
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2010 Å2
ΔGint-25 kcal/mol
Surface area18760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.595, 63.676, 124.625
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-A1BZD / (morpholin-4-yl)[(4R,8M)-8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methanone


Mass: 366.295 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H13F3N4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 348 / 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: 2.14 Å3/Da / Density % sol: 42.4 %
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: Aug 2, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 1.95→50 Å / Num. obs: 32545 / % possible obs: 93.7 % / Redundancy: 6 % / Rmerge(I) obs: 0.105 / Χ2: 1.005 / Net I/σ(I): 8.3 / Num. measured all: 193833
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
1.95-1.985.40.76711880.924170
1.98-2.025.40.65913590.969178.9
2.02-2.065.60.55515740.994192
2.06-2.16.10.52715851.076193.3
2.1-2.156.10.44216130.999194.4
2.15-2.26.10.37916161.009193.6
2.2-2.2560.33716241.068195.5
2.25-2.316.10.31616171.026195
2.31-2.386.10.26216250.998193.9
2.38-2.466.10.21216281.007194
2.46-2.5460.19116311.003194.2
2.54-2.6560.17516311.007195.5
2.65-2.7760.14616320.989194.4
2.77-2.9160.12116511.01195.2
2.91-3.160.09716700.998196
3.1-3.3360.07317121.001198.1
3.33-3.6760.05917351.001198.8
3.67-4.26.10.05217620.993199.5
4.2-5.296.10.04717850.994199.6
5.29-505.90.04719071199.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0419refinement
HKL-2000data scaling
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.95→35.46 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.94 / SU B: 7.57 / SU ML: 0.109 / Cross valid method: THROUGHOUT / ESU R: 0.183 / ESU R Free: 0.155 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.21323 1652 5.1 %RANDOM
Rwork0.17532 ---
obs0.17727 30848 93.54 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 27.875 Å2
Baniso -1Baniso -2Baniso -3
1--0.42 Å2-0 Å2-0 Å2
2--0.11 Å2-0 Å2
3---0.31 Å2
Refinement stepCycle: 1 / Resolution: 1.95→35.46 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3517 0 69 348 3934
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0123695
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0931.6915014
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.535446
X-RAY DIFFRACTIONr_dihedral_angle_2_deg3.422536
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.23810659
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0890.2540
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022807
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_it1.0281.7711757
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.7843.1712194
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.4681.9911938
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined5.51121.785927
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: 1.951→2.001 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.308 91 -
Rwork0.249 1702 -
obs--71.07 %
Refinement TLS params.Method: refined / Origin x: 13.99 Å / Origin y: -4.7559 Å / Origin z: -18.8343 Å
111213212223313233
T0.0191 Å20.0027 Å20.0066 Å2-0.0118 Å2-0.0028 Å2--0.0036 Å2
L0.37 °20.0577 °2-0.0706 °2-1.8563 °2-0.0776 °2--0.8497 °2
S0.0018 Å °0.0627 Å °-0.0179 Å °-0.1478 Å °0.0046 Å °-0.0686 Å °-0.0031 Å °0.0096 Å °-0.0064 Å °

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