PDB-3oj8: Alpha-Ketoheterocycle Inhibitors of Fatty Acid Amide Hydrolase Co...

ID or keywords:

Entry

Database: PDB / ID: 3oj8

Title

Alpha-Ketoheterocycle Inhibitors of Fatty Acid Amide Hydrolase Containing Additional Conformational Contraints in the Acyl Side Chain

Components

Fatty-acid amide hydrolase 1

Keywords

Hydrolase/Hydrolase Inhibitor / protein-inhibitor complex / FAAH / oxazole / enantiomer / Serine Hydrolase / Membrane / Hydrolase-Hydrolase Inhibitor complex

Function / homology

Function and homology information

Arachidonic acid metabolism / fatty acid amide hydrolase / fatty acid amide hydrolase activity / monoacylglycerol catabolic process / monoacylglycerol lipase activity / amidase activity / fatty acid catabolic process / Hydrolases; Acting on ester bonds; Carboxylic-ester hydrolases / hydrolase activity, acting on ester bonds / organelle membrane ...
Similarity search - Function

Biological species

Rattus norvegicus (Norway rat)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.9 Å

Authors

Mileni, M. / Stevens, R.C. / Boger, D.L.

Citation

Journal: J.Med.Chem. / Year: 2011
Title: alpha-Ketoheterocycle Inhibitors of Fatty Acid Amide Hydrolase Containing Additional Conformational Contraints in the Acyl Side Chain
Authors: Ezzili, C. / Mileni, M. / McGlinchey, N. / Long, J.Z. / Kinsey, S.G. / Hochstatter, D.G. / Stevens, R.C. / Lichtman, A.H. / Cravatt, B.F. / Bilsky, E.J. / Boger, D.L.

History

Deposition	Aug 20, 2010	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Jul 6, 2011	Provider: repository / Type: Initial release
Revision 1.1	Jul 13, 2011	Group: Version format compliance

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	3oj8.cif.gz	438 KB	Display	PDBx/mmCIF format
PDB format	pdb3oj8.ent.gz	373.2 KB	Display	PDB format
PDBx/mmJSON format	3oj8.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Summary document	3oj8_validation.pdf.gz	943.7 KB	Display	wwPDB validaton report
Full document	3oj8_full_validation.pdf.gz	949.6 KB	Display
Data in XML	3oj8_validation.xml.gz	47.8 KB	Display
Data in CIF	3oj8_validation.cif.gz	72.7 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/oj/3oj8 ftp://data.pdbj.org/pub/pdb/validation_reports/oj/3oj8	HTTPS FTP

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Related structure data

Related structure data	2vya 2wap 2wj1 2wj2 3k7f 3lj6
Similar structure data	2wj1-d 3qj9-d 1mt5-3 3qkv-d 1mt5-6 3pr0-d 1mt5-4 4hbp-d 1mt5-7 1mt5-5 1mt5-8 2vya-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

Deposited unit

A: Fatty-acid amide hydrolase 1

B: Fatty-acid amide hydrolase 1

hetero molecules

127 kDa, 2 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)	103.299, 103.299, 253.355
Angle α, β, γ (deg.)	90.00, 90.00, 120.00
Int Tables number	154
Space group name H-M	P3₂21

#1: Protein	Fatty-acid amide hydrolase 1 / Oleamide hydrolase 1 / Anandamide amidohydrolase 1 Mass: 63111.664 Da / Num. of mol.: 2 / Fragment: UNP residues 30-579 / Mutation: L192F, F194Y, A377T, S435N, I491V, V495M Source method: isolated from a genetically manipulated source Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Faah, faah-1, Faah1 / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 AI / References: UniProt: P97612, fatty acid amide hydrolase
#2: Chemical	ChemComp-OJ8 / (S)-[(2S)-6-phenoxy-1,2,3,4-tetrahydronaphthalen-2-yl](5-pyridin-2-yl-1,3-oxazol-2-yl)methanol Mass: 398.454 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂₅H₂₂N₂O₃
#3: Chemical	ChemComp-CL / CHLORIDE ION Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 985 / Source method: isolated from a natural source / Formula: H₂O

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Experiment

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

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Sample preparation

Crystal	Density Matthews: 3.09 Å³/Da / Density % sol: 60.21 %
Crystal grow	Temperature: 287 K / Method: vapor diffusion, sitting drop / pH: 5.5 Details: 30% PEG400, 100mM MES, 100mM KCl, 100mM NaF, 8% Polypropylene Glycol P400 , pH 5.5, VAPOR DIFFUSION, SITTING DROP, temperature 287K

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Data collection

Diffraction	Mean temperature: 100 K
Diffraction source	Source: SYNCHROTRON / Site: SSRL / Beamline: BL11-1 / Wavelength: 0.97945 Å
Detector	Type: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Nov 27, 2009
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.97945 Å / Relative weight: 1
Reflection	Resolution: 1.9→40 Å / Num. all: 124032 / Num. obs: 118630 / % possible obs: 95.6 % / Observed criterion σ(I): -3 / Redundancy: 6.2 % / B_iso Wilson estimate: 19.9 Å² / R_merge(I) obs: 0.094 / Net I/σ(I): 12.9
Reflection shell	Resolution: 1.9→1.96 Å / Redundancy: 5.7 % / R_merge(I) obs: 0.62 / Mean I/σ(I) obs: 2.6 / Num. unique all: 10871 / % possible all: 87.4

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Processing

Software

Name	Version	Classification
XDS		data scaling
PHASER		phasing
PHENIX	(phenix.refine: 1.6.2_432)	refinement
XDS		data reduction
XSCALE		data scaling

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT / Resolution: 1.9→39.528 Å / SU ML: 0.19 / σ(F): 1.99 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection
R_free	0.1848	5970	5.03 %
R_work	0.1544	-	-
obs	0.1559	118622	95.66 %
all	-	124032	-

Solvent computation

Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / B_sol: 36.139 Å² / k_sol: 0.341 e/Å³

Displacement parameters

	B_aniso -1	B_aniso -2	B_aniso -3
1-	0.6758 Å²	-0 Å²	-0 Å²
2-	-	0.6758 Å²	-0 Å²
3-	-	-	-1.3516 Å²

Refinement step

Cycle: LAST / Resolution: 1.9→39.528 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	8401	0	61	985	9447

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.013	8757
X-RAY DIFFRACTION	f_angle_d	1.644	11911
X-RAY DIFFRACTION	f_dihedral_angle_d	14.157	3317
X-RAY DIFFRACTION	f_chiral_restr	0.127	1330
X-RAY DIFFRACTION	f_plane_restr	0.009	1540

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 (%)
1.9-1.9216	0.2503	173	0.2156	3368	X-RAY DIFFRACTION	87
1.9216-1.9442	0.266	178	0.2161	3375	X-RAY DIFFRACTION	87
1.9442-1.9679	0.2086	167	0.1983	3418	X-RAY DIFFRACTION	88
1.9679-1.9929	0.2417	181	0.1939	3506	X-RAY DIFFRACTION	89
1.9929-2.0191	0.2228	180	0.1848	3476	X-RAY DIFFRACTION	90
2.0191-2.0467	0.2253	181	0.1858	3535	X-RAY DIFFRACTION	91
2.0467-2.076	0.2228	195	0.1774	3590	X-RAY DIFFRACTION	92
2.076-2.107	0.2265	181	0.172	3678	X-RAY DIFFRACTION	93
2.107-2.1399	0.2081	194	0.1687	3595	X-RAY DIFFRACTION	94
2.1399-2.175	0.2042	207	0.1604	3685	X-RAY DIFFRACTION	95
2.175-2.2125	0.1853	201	0.1593	3712	X-RAY DIFFRACTION	96
2.2125-2.2527	0.193	209	0.1568	3753	X-RAY DIFFRACTION	97
2.2527-2.296	0.2064	190	0.1553	3847	X-RAY DIFFRACTION	97
2.296-2.3429	0.2056	206	0.1515	3752	X-RAY DIFFRACTION	97
2.3429-2.3938	0.2132	207	0.153	3771	X-RAY DIFFRACTION	98
2.3938-2.4495	0.187	237	0.142	3802	X-RAY DIFFRACTION	98
2.4495-2.5107	0.1798	183	0.1495	3848	X-RAY DIFFRACTION	98
2.5107-2.5786	0.1815	212	0.1567	3839	X-RAY DIFFRACTION	98
2.5786-2.6545	0.1995	207	0.1501	3816	X-RAY DIFFRACTION	98
2.6545-2.7401	0.2179	208	0.1512	3849	X-RAY DIFFRACTION	98
2.7401-2.838	0.1676	188	0.1532	3865	X-RAY DIFFRACTION	99
2.838-2.9516	0.2014	197	0.1548	3914	X-RAY DIFFRACTION	99
2.9516-3.0859	0.1867	221	0.1494	3840	X-RAY DIFFRACTION	98
3.0859-3.2485	0.1724	205	0.1462	3893	X-RAY DIFFRACTION	99
3.2485-3.452	0.1607	214	0.1477	3931	X-RAY DIFFRACTION	99
3.452-3.7183	0.1629	203	0.1411	3919	X-RAY DIFFRACTION	99
3.7183-4.0921	0.1727	201	0.1392	3943	X-RAY DIFFRACTION	99
4.0921-4.6835	0.1613	204	0.1343	3967	X-RAY DIFFRACTION	99
4.6835-5.8975	0.147	219	0.147	4013	X-RAY DIFFRACTION	99
5.8975-39.5363	0.1724	221	0.1665	4152	X-RAY DIFFRACTION	98

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	0.5337	-0.1074	0.4338	0.624	-0.0199	0.6992	-0.1732	0.2971	-0.0269	-0.2885	0.1543	0.33	-0.1697	-0.0314	0.0529	0.2725	-0.0366	-0.0758	0.2835	0.0191	0.1758	23.6614	-32.6794	-14.4771
2	0.6344	-0.2655	0.2128	1.0826	-0.3904	0.2439	-0.0692	0.1446	0.0421	-0.26	0.0159	0.1114	-0.1265	-0.1135	0.0303	0.196	0.0201	-0.0456	0.1924	0.0448	0.1417	26.9619	-19.4725	-6.9281
3	0.7207	-0.7575	-0.9338	2.8907	0.7732	1.2945	0.0812	0.2868	0.0629	0.0833	0.216	0.2383	-0.0355	-0.3961	-0.241	0.1972	0.0861	-0.0825	0.2712	0.01	0.3347	15.8813	-18.4577	1.1421
4	0.2814	-0.0877	-0.0394	0.4213	0.1982	0.7102	-0.0093	0.0918	-0.0172	-0.0648	-0.014	0.0672	-0.0318	-0.073	0.0205	0.0402	-0.0056	-0.0097	0.0887	0.0034	0.0401	31.431	-33.2319	1.1279
5	0.1376	0.0775	0.0085	-0.0109	0.0293	0.5128	-0.0263	0.0632	0.0052	-0.0034	0.0019	0.0416	-0.0484	-0.1062	0.0081	0.1253	0.0132	0.0061	0.1536	0.0186	0.1212	29.4268	-28.031	13.937
6	0.3134	-0.0195	-0.0364	0.5803	-0.0148	0.5464	0.0095	0.0212	-0.019	0.0129	0.0031	-0.1044	-0.0162	0.1217	0.0221	0.0762	-0.0161	0.0113	0.1375	0.0094	0.0945	48.9686	-32.5277	11.9907
7	0.3324	0.0846	-0.1644	0.6074	-0.049	0.6873	-0.0197	0.0208	-0.029	-0.0326	-0.0005	-0.102	0.0329	0.1245	0.0198	0.0601	0.0108	0.0111	0.1234	0.0017	0.086	49.4578	-39.1478	10.6547
8	0.9636	0.5921	-0.4579	1.4868	-1.7488	2.1172	-0.1569	0.2683	0.3785	0.1173	0.1018	0.2263	-0.378	-0.1745	0.019	0.2317	-0.0375	0.0134	0.1867	0.0155	0.2373	47.6621	-13.6097	7.0808
9	0.2156	0.0902	0.1288	0.246	-0.3383	0.7281	-0.0407	-0.142	-0.0578	0.1277	-0.086	-0.0034	-0.0806	-0.0184	0.0998	0.1363	-0.001	-0.0227	0.2359	0.0028	0.1305	39.8551	-37.7274	64.1445
10	0.4307	0.1114	-0.0767	0.4663	0.1863	0.269	-0.0073	-0.1389	0.0389	0.0782	-0.0025	0.0514	-0.0679	0.024	0.0087	0.1441	-0.0031	-0.0047	0.1894	-0.0285	0.131	31.8443	-25.9171	59.1762
11	1.4575	1.1887	0.594	1.9534	1.1489	1.7766	0.0869	-0.1332	-0.12	-0.0046	0.0289	-0.2695	-0.4021	0.3344	-0.1222	0.2425	-0.0732	-0.0157	0.224	-0.0322	0.2453	41.4488	-19.3945	51.8593
12	0.0878	-0.0055	0.1021	0.2764	-0.0683	0.4816	0.0016	-0.0273	-0.0342	0.0212	-0.0016	-0.0245	-0.0154	0.0233	0.0009	0.0797	0.0006	0.0059	0.1184	0.0033	0.1058	32.3718	-38.3869	48.3174
13	0.2624	-0.0048	-0.0754	0.1901	-0.2568	0.507	0.0282	-0.0301	0.0006	-0.0387	-0.0294	0.0065	-0.0685	0.0426	0.0016	0.1312	-0.0017	0.0026	0.1462	0.0037	0.1269	31.683	-30.2527	37.069
14	0.3661	0.0575	-0.0218	0.5363	-0.0733	0.6488	-0.0294	0.0441	0.0102	0.0104	0.02	0.0795	-0.0043	-0.1263	0.0045	0.0813	-0.0079	0.0041	0.1358	0.0023	0.111	15.5029	-41.9349	37.2458
15	0.5866	-0.0074	-0.2396	0.2645	-0.061	0.4198	-0.0389	0.0622	-0.0741	-0.0294	0.0175	0.02	0.0572	-0.0962	0.0222	0.0226	-0.0202	0.0077	0.0556	-0.0125	0.0448	17.5263	-48.532	37.2041
16	1.8504	-0.5786	0.2252	1.042	0.4672	0.3537	-0.0262	-0.5336	0.2403	0.301	-0.045	0.0131	-0.2227	-0.1801	0.0674	0.1815	0.0541	0.0058	0.2319	-0.0377	0.223	10.7134	-24.8292	47.7594

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details
1	X-RAY DIFFRACTION	1	(chain A and resid 33:72)
2	X-RAY DIFFRACTION	2	(chain A and resid 73:120)
3	X-RAY DIFFRACTION	3	(chain A and resid 121:133)
4	X-RAY DIFFRACTION	4	(chain A and resid 134:265)
5	X-RAY DIFFRACTION	5	(chain A and resid 266:315)
6	X-RAY DIFFRACTION	6	(chain A and resid 316:399)
7	X-RAY DIFFRACTION	7	(chain A and resid 400:565)
8	X-RAY DIFFRACTION	8	(chain A and resid 566:577)
9	X-RAY DIFFRACTION	9	(chain B and resid 32:72)
10	X-RAY DIFFRACTION	10	(chain B and resid 73:120)
11	X-RAY DIFFRACTION	11	(chain B and resid 121:133)
12	X-RAY DIFFRACTION	12	(chain B and resid 134:265)
13	X-RAY DIFFRACTION	13	(chain B and resid 266:315)
14	X-RAY DIFFRACTION	14	(chain B and resid 316:399)
15	X-RAY DIFFRACTION	15	(chain B and resid 400:565)
16	X-RAY DIFFRACTION	16	(chain B and resid 566:577)

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