PDB-7n3l: Co-complex CYP46A1 with 0420 (compound 6)

ID or keywords:

Entry

Database: PDB / ID: 7n3l

Title

Co-complex CYP46A1 with 0420 (compound 6)

Components

Cholesterol 24-hydroxylase

Keywords

OXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR /

cyp46a1 / ch24h / sbdd /

drug discovery / OXIDOREDUCTASE-OXIDOREDUCTASE 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 / 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: 1.631 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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Download

PDBx/mmCIF format	7n3l.cif.gz	191.9 KB	Display	PDBx/mmCIF format
PDB format	pdb7n3l.ent.gz	143.5 KB	Display	PDB format
PDBx/mmJSON format	7n3l.json.gz		Tree view	PDBx/mmJSON format
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Validation report

Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/n3/7n3l ftp://data.pdbj.org/pub/pdb/validation_reports/n3/7n3l	HTTPS FTP

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Related structure data

Related structure data	7n3mC 7lrlS S: Starting model for refinement C: citing same article (ref.)
Similar structure data	7ls4-d 7lrl-d 6ldl-d 3t3s-1 3tl8-3 3tl8-4 7n3m-d 1z10-4 6vlt-4 7ls3-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

A: Cholesterol 24-hydroxylase

hetero molecules

55.6 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)	58.494, 63.679, 124.637
Angle α, β, γ (deg.)	90.000, 90.000, 90.000
Int Tables number	19
Space group name H-M	P2₁2₁2₁

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Protein , 1 types, 1 molecules A

#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

#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

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Non-polymers , 5 types, 371 molecules

#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-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂H₆O₂
#4: Chemical	ChemComp-04Y / N-cyclopropyl-1-(4-phenylpyridin-3-yl)piperidine-4-carboxamide Mass: 321.416 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₂₀H₂₃N₃O / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical	ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₃H₈O₃
#6: Water	ChemComp-HOH / water / Water Mass: 18.015 Da / Num. of mol.: 366 / Source method: isolated from a natural source / Formula: H₂O

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Details

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: 2.13 Å³/Da / Density % sol: 42.31 %
Crystal grow	Temperature: 290 K / Method: vapor diffusion, hanging drop / Details: 17.5% PEG 3350, 0.4M Calcium chloride

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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: May 23, 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: 1.63→45 Å / Num. obs: 58262 / % possible obs: 99.2 % / Redundancy: 6.8 % / R_merge(I) obs: 0.104 / Net I/σ(I): 18.2
Reflection shell	Resolution: 1.63→1.66 Å / R_merge(I) obs: 0.98 / Mean I/σ(I) obs: 2.2 / Num. unique obs: 5648 / % possible all: 99

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Processing

Software

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

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 7LRL

7lrl

Resolution: 1.631→35.436 Å / Cor.coef. F_o:F_c: 0.965 / Cor.coef. F_o:F_c free: 0.953 / SU B: 3.584 / SU ML: 0.065 / Cross valid method: FREE R-VALUE / ESU R: 0.088 / ESU R Free: 0.089
Details: Hydrogens have been added in their riding positions

	R_factor	Num. reflection	% reflection
R_free	0.2004	2876	4.936 %
R_work	0.1669	55386	-
all	0.169	-	-
obs	-	58262	99.161 %

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: 20.756 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	-0.309 Å²	-0 Å²	0 Å²
2-	-	0.299 Å²	-0 Å²
3-	-	-	0.01 Å²

Refinement step

Cycle: LAST / Resolution: 1.631→35.436 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	3499	0	81	366	3946

Refine LS restraints

Refine-ID	Type	Dev ideal	Dev ideal target	Number
X-RAY DIFFRACTION	r_bond_refined_d	0.013	0.013	3700
X-RAY DIFFRACTION	r_bond_other_d	0.001	0.017	3597
X-RAY DIFFRACTION	r_angle_refined_deg	1.816	1.683	5012
X-RAY DIFFRACTION	r_angle_other_deg	1.514	1.599	8268
X-RAY DIFFRACTION	r_dihedral_angle_1_deg	5.843	5	445
X-RAY DIFFRACTION	r_dihedral_angle_2_deg	30.733	20.725	207
X-RAY DIFFRACTION	r_dihedral_angle_3_deg	14.375	15	662
X-RAY DIFFRACTION	r_dihedral_angle_4_deg	16.542	15	36
X-RAY DIFFRACTION	r_chiral_restr	0.098	0.2	451
X-RAY DIFFRACTION	r_gen_planes_refined	0.011	0.02	4124
X-RAY DIFFRACTION	r_gen_planes_other	0.006	0.02	896
X-RAY DIFFRACTION	r_nbd_refined	0.223	0.2	786
X-RAY DIFFRACTION	r_symmetry_nbd_other	0.177	0.2	3498
X-RAY DIFFRACTION	r_nbtor_refined	0.175	0.2	1829
X-RAY DIFFRACTION	r_symmetry_nbtor_other	0.082	0.2	1839
X-RAY DIFFRACTION	r_xyhbond_nbd_refined	0.207	0.2	249
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_other	0.149	0.2	1
X-RAY DIFFRACTION	r_symmetry_nbd_refined	0.323	0.2	12
X-RAY DIFFRACTION	r_nbd_other	0.22	0.2	56
X-RAY DIFFRACTION	r_symmetry_xyhbond_nbd_refined	0.192	0.2	24
X-RAY DIFFRACTION	r_mcbond_it	0.805	0.984	1747
X-RAY DIFFRACTION	r_mcbond_other	0.802	0.983	1746
X-RAY DIFFRACTION	r_mcangle_it	1.3	1.469	2182
X-RAY DIFFRACTION	r_mcangle_other	1.3	1.469	2183
X-RAY DIFFRACTION	r_scbond_it	1.558	1.218	1953
X-RAY DIFFRACTION	r_scbond_other	1.559	1.219	1954
X-RAY DIFFRACTION	r_scangle_it	2.383	1.741	2820
X-RAY DIFFRACTION	r_scangle_other	2.383	1.741	2821
X-RAY DIFFRACTION	r_lrange_it	5.264	13.115	4329
X-RAY DIFFRACTION	r_lrange_other	5.161	12.511	4254

LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)	R_factor R_free	Num. reflection R_free	R_factor R_work	Num. reflection R_work	R_factor all	Num. reflection all	Fsc free	Fsc work	% reflection obs (%)	WR_factor R_work
1.631-1.673	0.302	208	0.251	3940	0.254	4271	0.83	0.852	97.1201	0.221
1.673-1.719	0.237	207	0.226	3889	0.227	4167	0.896	0.901	98.2961	0.192
1.719-1.769	0.253	193	0.22	3797	0.221	4062	0.888	0.905	98.2275	0.186
1.769-1.823	0.257	176	0.202	3714	0.204	3948	0.903	0.922	98.5309	0.17
1.823-1.883	0.213	171	0.178	3613	0.18	3835	0.938	0.943	98.6701	0.152
1.883-1.949	0.22	182	0.181	3482	0.183	3693	0.93	0.939	99.2147	0.159
1.949-2.022	0.206	167	0.169	3404	0.171	3592	0.942	0.946	99.4154	0.151
2.022-2.104	0.239	160	0.157	3273	0.161	3449	0.934	0.961	99.5361	0.145
2.104-2.197	0.193	184	0.155	3121	0.157	3326	0.956	0.963	99.3686	0.145
2.197-2.304	0.173	144	0.142	3008	0.144	3156	0.958	0.967	99.8733	0.135
2.304-2.428	0.187	162	0.143	2866	0.146	3033	0.959	0.968	99.8351	0.137
2.428-2.575	0.172	143	0.148	2731	0.15	2876	0.962	0.966	99.9305	0.143
2.575-2.752	0.205	159	0.159	2558	0.162	2718	0.956	0.962	99.9632	0.159
2.752-2.971	0.182	107	0.166	2423	0.166	2532	0.958	0.963	99.921	0.17
2.971-3.252	0.2	127	0.158	2219	0.161	2347	0.958	0.966	99.9574	0.17
3.252-3.632	0.188	103	0.156	2023	0.158	2129	0.956	0.963	99.8591	0.172
3.632-4.186	0.176	102	0.147	1794	0.149	1897	0.969	0.971	99.9473	0.167
4.186-5.109	0.189	81	0.145	1546	0.147	1627	0.969	0.977	100	0.169
5.109-7.152	0.194	60	0.192	1237	0.192	1298	0.967	0.962	99.923	0.217
7.152-35.436	0.197	40	0.203	748	0.203	792	0.969	0.967	99.4949	0.236

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	0.1045	0.2912	-0.0961	2.5688	1.1193	1.3915	0.0149	0.0062	0.0138	-0.1897	0.0677	-0.1834	-0.1824	0.1504	-0.0826	0.0737	0.0076	0.03	0.0763	0.0448	0.0905	17.9455	9.9325	-19.6455
2	1.3192	-0.9225	1.3013	2.7213	-2.0471	3.186	-0.0051	0.135	-0.0628	-0.2693	-0.0097	0.0395	0.1606	-0.0065	0.0148	0.0607	-0.0108	-0.0023	0.0269	-0.0215	0.0396	11.3057	-20.8087	-21.7204
3	1.3512	0.9181	0.4746	6.3265	2.0182	2.0568	0.0085	-0.0604	-0.0694	0.0827	0.0185	-0.1698	0.0682	0.0643	-0.0269	0.0986	0.0121	0.0296	0.1208	-0.0009	0.0948	26.7247	-9.6119	-25.7219
4	6.5592	0.326	0.532	1.7268	0.3485	1.9315	-0.0658	0.3396	-0.2104	-0.4189	0.0985	-0.0762	-0.0197	0.0383	-0.0327	0.1873	-0.0027	0.0435	0.107	-0.0012	0.0491	17.4348	-9.0498	-39.1353
5	1.1825	0.4177	-1.0575	1.4739	-1.5117	5.0436	-0.1137	0.0793	-0.1468	-0.12	0.0692	0.1597	0.2156	-0.3106	0.0446	0.0237	-0.0098	0.0037	0.0215	-0.0091	0.055	7.2834	-14.0997	-14.5187
6	0.5246	0.7033	-0.0227	3.4484	-0.3811	0.4046	0.0665	-0.077	0.1006	0.1792	-0.0386	0.1424	-0.1377	-0.0505	-0.028	0.0537	0.0081	0.0208	0.0186	-0.0117	0.0208	10.9726	5.5258	-9.5804
7	1.7721	-0.3691	1.1049	2.6044	-0.68	1.41	-0.0165	0.0076	-0.1068	0.0574	0.0393	-0.0534	0.0289	-0.0533	-0.0228	0.0085	0.0015	0.0012	0.0282	-0.0126	0.0137	14.7129	-16.5181	-10.4273

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection	Auth asym-ID	Auth seq-ID
1	X-RAY DIFFRACTION	1	ALL	A	28 - 146
2	X-RAY DIFFRACTION	2	ALL	A	147 - 208
3	X-RAY DIFFRACTION	3	ALL	A	209 - 226
4	X-RAY DIFFRACTION	4	ALL	A	236 - 289
5	X-RAY DIFFRACTION	5	ALL	A	290 - 350
6	X-RAY DIFFRACTION	6	ALL	A	351 - 439
7	X-RAY DIFFRACTION	7	ALL	A	440 - 489

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