PDB-7n3m: Co-complex CYP46A1 with 0431 (compound 17)

ID or keywords:

Entry

Database: PDB / ID: 7n3m

Title

Co-complex CYP46A1 with 0431 (compound 17)

Components

Cholesterol 24-hydroxylase

Keywords

HYDROLASE /

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 / Synthesis of bile acids and bile salts via 24-hydroxycholesterol / progesterone metabolic process / sterol metabolic process / bile acid biosynthetic process / regulation of long-term synaptic potentiation /

steroid hydroxylase activity ...
Similarity search - Function

Biological species

Homo sapiens (human)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.698 Å

Authors

Lane, W. / Yano, J.

Citation

Journal: J.Med.Chem. / Year: 2022
Title: Discovery of Novel 3-Piperidinyl Pyridine Derivatives as Highly Potent and Selective Cholesterol 24-Hydroxylase (CH24H) Inhibitors.
Authors: Kajita, Y. / Ikeda, S. / Yoshikawa, M. / Fukuda, H. / Watanabe, E. / Yano, J. / Lane, W. / Miyamoto, M. / Ishii, T. / Nishi, T. / Koike, T.

History

Deposition	Jun 1, 2021	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Feb 23, 2022	Provider: repository / Type: Initial release
Revision 1.1	Mar 16, 2022	Group: Database references / Category: citation / citation_author Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2	Oct 18, 2023	Group: Data collection / Refinement description Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

Structure viewer	Molecule: MolmilJmol/JSmol

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PDBx/mmCIF format	7n3m.cif.gz	200.2 KB	Display	PDBx/mmCIF format
PDB format	pdb7n3m.ent.gz		Display	PDB format
PDBx/mmJSON format	7n3m.json.gz		Tree view	PDBx/mmJSON format
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Validation report

Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/n3/7n3m ftp://data.pdbj.org/pub/pdb/validation_reports/n3/7n3m	HTTPS FTP

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Related structure data

Related structure data	7n3lC 7lrlS C: citing same article (ref.) S: Starting model for refinement
Similar structure data	7ls3-d 7lrl-d 7ls4-d 7n3l-d 5ylw-d 3t3s-1 5e58-5 4ejg-7 5e58-6 6l8i-d Search similar-shape structures by Omokage search (details) Similarity search - Function & homologyF&H Search Similarity search - FunctionF&H Search Similarity search - HomologyF&H Search

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Links

PDB pages	PDBj / wwPDB / NCBI
Related items in Molecule of the Month	#92 - Aug 2007 Anabolic Steroids similarity (1) #155 - Nov 2012 Vitamin D Receptor similarity (2) #258 - Jun 2021 Glucocorticoid Receptor and Dexamethasone similarity (1)

Deposited unit

AAA: Cholesterol 24-hydroxylase

hetero molecules

55.4 kDa, 1 polymers
Search similar-shape structures of this assembly by Omokage search (details)

1

Idetical with deposited unit
defined by author&software

Unit cell

Length a, b, c (Å)	58.572, 63.717, 125.061
Angle α, β, γ (deg.)	90.000, 90.000, 90.000
Int Tables number	19
Space group name H-M	P2₁2₁2₁

#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 / Heme B Mass: 616.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₃₄H₃₂FeN₄O₄
#3: Chemical	ChemComp-05D / N,N-dimethyl-1-[4-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl]piperidine-4-carboxamide Mass: 313.397 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₁₇H₂₃N₅O / Feature type: SUBJECT OF INVESTIGATION
#4: Water	ChemComp-HOH / water / Water Mass: 18.015 Da / Num. of mol.: 390 / Source method: isolated from a natural source / Formula: H₂O
Has ligand of interest	Y

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Experiment

Experiment	Method: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

Crystal	Density Matthews: 2.33 Å³/Da / Density % sol: 42.62 %
Crystal grow	Temperature: 290 K / Method: vapor diffusion, hanging drop / Details: 17.5% PEG 3350, 0.4M Calcium Cl

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Data collection

Diffraction	Mean temperature: 100 K / Serial crystal experiment: N
Diffraction source	Source: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.976 Å
Detector	Type: ADSC QUANTUM 315r / Detector: CCD / Date: Aug 8, 2012
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.976 Å / Relative weight: 1
Reflection	Resolution: 1.698→45 Å / Num. obs: 51775 / % possible obs: 98.74 % / Redundancy: 6.6 % / R_sym value: 0.109 / Net I/σ(I): 15.8
Reflection shell	Resolution: 1.698→1.73 Å / Mean I/σ(I) obs: 1.86 / Num. unique obs: 4610 / R_sym value: 0.764

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Processing

Software

Name	Version	Classification
REFMAC	5.8.0267	refinement
HKL-2000		data reduction
HKL-2000		data scaling
REFMAC		phasing

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 7LRL

7lrl

Resolution: 1.698→44.669 Å / Cor.coef. F_o:F_c: 0.965 / Cor.coef. F_o:F_c free: 0.955 / WR_factor R_free: 0.195 / WR_factor R_work: 0.169 / SU B: 4.357 / SU ML: 0.069 / Average fsc free: 0.9379 / Average fsc work: 0.9469 / Cross valid method: FREE R-VALUE / ESU R: 0.1 / ESU R Free: 0.095
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection
R_free	0.1918	2532	4.89 %
R_work	0.1642	49243	-
all	0.166	-	-
obs	-	51775	98.583 %

Solvent computation

Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT

Displacement parameters

B_iso mean: 22.586 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	0.811 Å²	0 Å²	0 Å²
2-	-	-0.381 Å²	0 Å²
3-	-	-	-0.431 Å²

Refinement step

Cycle: LAST / Resolution: 1.698→44.669 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	3525	0	66	390	3981

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.015	0.013	3747
X-RAY DIFFRACTION	r_bond_other_d	0.001	0.017	3630
X-RAY DIFFRACTION	r_angle_refined_deg	1.9	1.68	5089
X-RAY DIFFRACTION	r_angle_other_deg	1.529	1.597	8343
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	5.876	5	457
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	31.849	20.853	211
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	14.345	15	670
X-RAY DIFFRACTION	r_dihedral_angle_4_deg	15.846	15	36
X-RAY DIFFRACTION	r_chiral_restr	0.101	0.2	458
X-RAY DIFFRACTION	r_gen_planes_refined	0.012	0.02	4224
X-RAY DIFFRACTION	r_gen_planes_other	0.008	0.02	917
X-RAY DIFFRACTION	r_nbd_refined	0.257	0.2	813
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.183	0.2	3515
X-RAY DIFFRACTION	r_nbtor_refined	0.175	0.2	1841
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.081	0.2	1832
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.239	0.2	274
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_other	0.036	0.2	3
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.166	0.2	13
X-RAY DIFFRACTION	r_nbd_other	0.227	0.2	55
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.203	0.2	15
X-RAY DIFFRACTION	r_mcbond_it	1.023	1.091	1774
X-RAY DIFFRACTION	r_mcbond_other	1.021	1.089	1773
X-RAY DIFFRACTION	r_mcangle_it	1.688	1.626	2219
X-RAY DIFFRACTION	r_mcangle_other	1.688	1.628	2220
X-RAY DIFFRACTION	r_scbond_it	1.681	1.365	1973
X-RAY DIFFRACTION	r_scbond_other	1.681	1.365	1974
X-RAY DIFFRACTION	r_scangle_it	2.697	1.949	2860
X-RAY DIFFRACTION	r_scangle_other	2.697	1.949	2860
X-RAY DIFFRACTION	r_lrange_it	4.473	13.922	4419
X-RAY DIFFRACTION	r_lrange_other	4.286	13.42	4320

LS refinement shell

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	Refine-ID	% reflection obs (%)
1.698-1.742	0.311	151	0.259	3126	X-RAY DIFFRACTION	86.1462
1.742-1.789	0.25	167	0.233	3417	X-RAY DIFFRACTION	95.7265
1.789-1.841	0.269	163	0.207	3472	X-RAY DIFFRACTION	99.5073
1.841-1.898	0.2	151	0.175	3354	X-RAY DIFFRACTION	100
1.898-1.96	0.186	172	0.167	3261	X-RAY DIFFRACTION	100
1.96-2.028	0.19	158	0.158	3142	X-RAY DIFFRACTION	100
2.028-2.105	0.234	150	0.157	3058	X-RAY DIFFRACTION	100
2.105-2.191	0.194	172	0.152	2910	X-RAY DIFFRACTION	100
2.191-2.288	0.191	142	0.15	2834	X-RAY DIFFRACTION	100
2.288-2.399	0.201	145	0.148	2682	X-RAY DIFFRACTION	100
2.399-2.529	0.175	141	0.143	2564	X-RAY DIFFRACTION	99.8892
2.529-2.681	0.172	144	0.152	2428	X-RAY DIFFRACTION	100
2.681-2.866	0.167	118	0.15	2306	X-RAY DIFFRACTION	99.9176
2.866-3.094	0.186	116	0.154	2154	X-RAY DIFFRACTION	99.956
3.094-3.388	0.213	98	0.162	1978	X-RAY DIFFRACTION	99.8557
3.388-3.785	0.193	93	0.158	1809	X-RAY DIFFRACTION	99.7378
3.785-4.366	0.167	91	0.152	1606	X-RAY DIFFRACTION	99.8823
4.366-5.334	0.168	73	0.156	1386	X-RAY DIFFRACTION	99.8631
5.334-7.492	0.196	50	0.199	1093	X-RAY DIFFRACTION	100
7.492-44.66	0.169	37	0.193	663	X-RAY DIFFRACTION	99.0099

Refinement TLS params.

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

ID	L11 (°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)
1	0.5506	0.1123	-0.0631	1.807	-0.0913	0.9069	0.0009	0.0674	-0.0117	-0.1332	0.0078	-0.0413	-0.0215	0.0055	-0.0086	0.0159	0.0094	0.0048	0.0252	-0.0002	0.0691	14.1424	-4.8959	-18.7957
2	0.4464	-0.0346	0.0009	1.246	-0.0933	0.419	-0.0092	0.0178	-0.0108	-0.0013	0.0125	-0.0261	-0.0078	-0.0392	-0.0033	0.0136	-0.0004	0.0098	0.0372	-0.0067	0.0929	11.8774	-4.4601	-12.4821

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection	Auth asym-ID	Auth seq-ID
1	X-RAY DIFFRACTION	1	ALL	AAA	28 - 87
2	X-RAY DIFFRACTION	1	ALL	AAA	-10000
3	X-RAY DIFFRACTION	1	ALL	AAA	-10000
4	X-RAY DIFFRACTION	1	ALL	AAA	-10000
5	X-RAY DIFFRACTION	1	ALL	AAA	-10000
6	X-RAY DIFFRACTION	1	ALL	AAA	-10000
7	X-RAY DIFFRACTION	1	ALL	AAA	-10000
8	X-RAY DIFFRACTION	2	ALL	SSS	1 - 392

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