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

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Basic information

Entry
Database: PDB / ID: 9nnm
TitleCrystal structure of CYP46A1 with 3-chloro-N-[(3M)-3-(1,3-oxazol-5-yl)-5-(trifluoromethyl)phenyl]benzamide (compound 3f)
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: 1.7 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

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
Water7,476415
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2060 Å2
ΔGint-28 kcal/mol
Surface area19100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.729, 63.853, 124.763
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-A1BZA / 3-chloro-N-[(3M)-3-(1,3-oxazol-5-yl)-5-(trifluoromethyl)phenyl]benzamide


Mass: 366.722 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H10ClF3N2O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 415 / 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: 2.15 Å3/Da / Density % sol: 42.76 %
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: Jun 10, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 1.7→50 Å / Num. obs: 52144 / % possible obs: 100 % / Redundancy: 4.9 % / Rmerge(I) obs: 0.11 / Χ2: 1.004 / Net I/σ(I): 6.6 / Num. measured all: 257449
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsΧ2Diffraction-ID% possible all
1.7-1.734.60.85625850.9741100
1.73-1.764.90.86625291.0011100
1.76-1.7950.75225800.9971100
1.79-1.8350.65225831.0351100
1.83-1.8750.5725861.0251100
1.87-1.9150.48725401.0221100
1.91-1.9650.39925881.021100
1.96-2.0250.3125920.9721100
2.02-2.0750.2525671.0031100
2.07-2.1450.21425720.9771100
2.14-2.2250.18326151.0191100
2.22-2.3150.16325690.9891100
2.31-2.4150.1326190.9681100
2.41-2.5450.11626050.9861100
2.54-2.750.11126070.9841100
2.7-2.914.90.10526141.0461100
2.91-3.24.90.0926381.0781100
3.2-3.664.80.06526371.0171100
3.66-4.614.80.04226890.9651100
4.61-504.70.0428291199.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0419refinement
HKL-2000data scaling
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→35.53 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.946 / SU B: 4.929 / SU ML: 0.08 / Cross valid method: THROUGHOUT / ESU R: 0.114 / ESU R Free: 0.107 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.21671 2566 4.9 %RANDOM
Rwork0.19109 ---
obs0.19238 49472 99.66 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 23.961 Å2
Baniso -1Baniso -2Baniso -3
1--0.27 Å20 Å2-0 Å2
2--0.19 Å20 Å2
3---0.08 Å2
Refinement stepCycle: 1 / Resolution: 1.7→35.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3488 0 68 415 3971
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0123668
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0121.694977
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4225443
X-RAY DIFFRACTIONr_dihedral_angle_2_deg3.382535
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.27910656
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0790.2537
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022778
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_it0.8011.4391742
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.4292.5722174
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.0691.6071926
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined5.38217.645815
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: 1.702→1.747 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.31 187 -
Rwork0.293 3486 -
obs--96.43 %
Refinement TLS params.Method: refined / Origin x: 13.941 Å / Origin y: -4.8599 Å / Origin z: -18.8087 Å
111213212223313233
T0.0205 Å20.0031 Å20.0092 Å2-0.0085 Å2-0.0008 Å2--0.0061 Å2
L0.4435 °20.0548 °2-0.0372 °2-1.568 °2-0.1169 °2--0.7086 °2
S0.0077 Å °0.0597 Å °-0.0158 Å °-0.1579 Å °-0.0072 Å °-0.0609 Å °-0.015 Å °0.0052 Å °-0.0005 Å °

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