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- PDB-9nna: Crystal structure of CYP46A1 with [(1R,5S)-3-oxa-8-azabicyclo[3.2... -

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Basic information

Entry
Database: PDB / ID: 9nna
TitleCrystal structure of CYP46A1 with [(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl][(4R,8M)-8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methanone (compound 3k)
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: 1.67 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)55,4443
Polymers54,4351
Non-polymers1,0092
Water5,116284
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1230 Å2
ΔGint-22 kcal/mol
Surface area18830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.478, 63.633, 124.615
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-A1BZE / [(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl][(4R,8M)-8-(1,3-oxazol-5-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methanone


Mass: 392.332 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H15F3N4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 284 / 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: 2.13 Å3/Da / Density % sol: 42.24 %
Crystal growTemperature: 293.15 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: Jun 4, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 1.67→50 Å / Num. obs: 54937 / % possible obs: 99.6 % / Redundancy: 6.8 % / Rmerge(I) obs: 0.102 / Χ2: 1.007 / Net I/σ(I): 9.5 / Num. measured all: 375606
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
1.67-1.74.10.75125410.969194.6
1.7-1.734.70.70826970.985198.4
1.73-1.765.80.72226770.992199.8
1.76-1.86.90.64127201.0081100
1.8-1.847.30.5427301.0131100
1.84-1.887.30.46127321.0171100
1.88-1.937.30.36827111.0391100
1.93-1.987.30.31327271.0231100
1.98-2.047.30.24827241.0081100
2.04-2.17.30.20427471.0111100
2.1-2.187.30.17227471.0131100
2.18-2.277.30.14227441.0011100
2.27-2.377.30.12827431.0111100
2.37-2.497.30.10327301.021100
2.49-2.657.30.09527891.0041100
2.65-2.867.20.08227550.991100
2.86-3.147.10.07727811.011100
3.14-3.66.80.06728091.0111100
3.6-4.536.70.05128460.9961100
4.53-506.70.03529870.983199.9

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
HKL-2000data scaling
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.67→30 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.948 / SU B: 4.302 / SU ML: 0.065 / Cross valid method: THROUGHOUT / ESU R: 0.137 / ESU R Free: 0.096 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.20739 2708 4.9 %RANDOM
Rwork0.17027 ---
obs0.17214 52157 99.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 9.055 Å2
Baniso -1Baniso -2Baniso -3
1-0.83 Å20 Å2-0 Å2
2---0.87 Å2-0 Å2
3---0.05 Å2
Refinement stepCycle: 1 / Resolution: 1.67→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3499 0 71 284 3854
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0193688
X-RAY DIFFRACTIONr_bond_other_d0.0010.022567
X-RAY DIFFRACTIONr_angle_refined_deg2.0612.0045014
X-RAY DIFFRACTIONr_angle_other_deg0.94636226
X-RAY DIFFRACTIONr_dihedral_angle_1_deg55451
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.90623.174167
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.53415651
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.6321534
X-RAY DIFFRACTIONr_chiral_restr0.0820.2548
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0214083
X-RAY DIFFRACTIONr_gen_planes_other0.0050.02783
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr3.8136255
X-RAY DIFFRACTIONr_sphericity_free16.713595
X-RAY DIFFRACTIONr_sphericity_bonded4.3156357
LS refinement shellResolution: 1.67→1.709 Å
RfactorNum. reflection% reflection
Rfree0.342 170 -
Rwork0.243 3335 -
obs--92.46 %
Refinement TLS params.Method: refined / Origin x: 14.066 Å / Origin y: -4.532 Å / Origin z: -18.905 Å
111213212223313233
T0.0234 Å20.0045 Å20.0055 Å2-0.0221 Å20.0003 Å2--0.0256 Å2
L0.3683 °2-0.0204 °2-0.0704 °2-1.6336 °2-0.0369 °2--0.7816 °2
S0.009 Å °0.0602 Å °-0.01 Å °-0.1216 Å °0.0083 Å °-0.0416 Å °-0.0147 Å °0.0017 Å °-0.0173 Å °

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