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- PDB-7ls3: Co-complex CYP46A1 with 8114 (3f) -

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Basic information

Entry
Database: PDB / ID: 7ls3
TitleCo-complex CYP46A1 with 8114 (3f)
ComponentsCholesterol 24-hydroxylase
KeywordsHYDROLASE / cyp46a1 / ch24h / sbdd / drug discovery
Function / homology
Function and homology information


cholesterol 24-hydroxylase / cholesterol 24-hydroxylase activity / protein localization to membrane raft / testosterone 16-beta-hydroxylase activity / bile acid biosynthetic process / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / progesterone metabolic process / sterol metabolic process / steroid hydroxylase activity / cholesterol catabolic process ...cholesterol 24-hydroxylase / cholesterol 24-hydroxylase activity / protein localization to membrane raft / testosterone 16-beta-hydroxylase activity / bile acid biosynthetic process / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / progesterone metabolic process / sterol metabolic process / steroid hydroxylase activity / cholesterol catabolic process / regulation of long-term synaptic potentiation / Endogenous sterols / xenobiotic metabolic process / presynapse / nervous system development / postsynapse / iron ion binding / dendrite / heme binding / 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 / Chem-YCJ / Cholesterol 24-hydroxylase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.15 Å
AuthorsLane, W. / Yano, J.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of Soticlestat, a Potent and Selective Inhibitor for Cholesterol 24-Hydroxylase (CH24H).
Authors: Koike, T. / Yoshikawa, M. / Ando, H.K. / Farnaby, W. / Nishi, T. / Watanabe, E. / Yano, J. / Miyamoto, M. / Kondo, S. / Ishii, T. / Kuroita, T.
History
DepositionFeb 17, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 25, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 8, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)55,4383
Polymers54,4351
Non-polymers1,0032
Water3,333185
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)58.349, 63.603, 123.107
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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-YCJ / (5-methyl-2-pyridin-4-yl-phenyl)-[4-oxidanyl-4-(phenylmethyl)piperidin-1-yl]methanone


Mass: 386.486 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H26N2O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 185 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 41.38 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 17.% PEG 3350, 0.35M Calcium Cl

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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: Mar 3, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.15→35.25 Å / Num. obs: 23172 / % possible obs: 96 % / Redundancy: 4 % / Rsym value: 0.105 / Net I/σ(I): 12.8
Reflection shellResolution: 2.15→2.19 Å / Mean I/σ(I) obs: 1.8 / Num. unique obs: 1178 / Rsym value: 0.714

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
REFMAC5.8.0267refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2Q9G

2q9g


Resolution: 2.15→35.25 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.929 / SU B: 14.566 / SU ML: 0.191 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.288 / ESU R Free: 0.217 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2439 1236 5.1 %RANDOM
Rwork0.1944 ---
obs0.197 23171 95.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 89.19 Å2 / Biso mean: 37.98 Å2 / Biso min: 15.19 Å2
Baniso -1Baniso -2Baniso -3
1--1.48 Å20 Å2-0 Å2
2--0.06 Å20 Å2
3---1.42 Å2
Refinement stepCycle: final / Resolution: 2.15→35.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3447 0 72 185 3704
Biso mean--21.86 38.36 -
Num. residues----429
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0123598
X-RAY DIFFRACTIONr_angle_refined_deg1.5071.6794871
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0745425
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.12521.055199
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.57115638
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.3531533
X-RAY DIFFRACTIONr_chiral_restr0.1220.2440
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022758
LS refinement shellResolution: 2.155→2.21 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.321 90 -
Rwork0.272 1627 -
all-1717 -
obs--92.96 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.618-0.1021-0.11342.3715-0.11671.41140.01560.1399-0.0045-0.2073-0.0105-0.0287-0.0429-0.0079-0.00510.08940.01-0.00570.033-0.00230.001513.603-5.005-18.75
23.0223-2.39681.02071.9417-1.31496.72760.2334-0.0202-0.0654-0.1791-0.01690.0726-0.14130.3821-0.21650.1268-0.0154-0.05550.0238-0.01070.046210.675-1.2-22.199
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A31 - 489
2X-RAY DIFFRACTION2A501

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