PDB-3k7f: Crystal Structure Analysis of a Phenhexyl/Oxazole/Carboxypyridine...

ID or keywords:

Entry

Database: PDB / ID: 3k7f

Title

Crystal Structure Analysis of a Phenhexyl/Oxazole/Carboxypyridine alpha-Ketoheterocycle Inhibitor Bound to a Humanized Variant of Fatty Acid Amide Hydrolase'

Components

Fatty-acid amide hydrolase 1

Keywords

HYDROLASE / protein-inhibitor complex / FAAH / oxazole / Membrane / Transmembrane

Function / homology

Function and homology information

Arachidonate metabolism / fatty acid amide hydrolase / regulation of trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / 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 ...
Similarity search - Function

Biological species

Rattus norvegicus (Norway rat)

Method

X-RAY DIFFRACTION /

SYNCHROTRON /

MOLECULAR REPLACEMENT / Resolution: 1.95 Å

Authors

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

Citation

Journal: J.Med.Chem. / Year: 2010
Title: X-ray crystallographic analysis of alpha-ketoheterocycle inhibitors bound to a humanized variant of fatty acid amide hydrolase.
Authors: Mileni, M. / Garfunkle, J. / Ezzili, C. / Kimball, F.S. / Cravatt, B.F. / Stevens, R.C. / Boger, D.L.

History

Deposition	Oct 13, 2009	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Dec 1, 2009	Provider: repository / Type: Initial release
Revision 1.1	Jul 13, 2011	Group: Version format compliance
Revision 1.2	Oct 13, 2021	Group: Database references / Derived calculations Category: database_2 / struct_conn ...database_2 / struct_conn / struct_ref_seq_dif / struct_site Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3	Sep 6, 2023	Group: Data collection / Refinement description Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4	Oct 30, 2024	Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	3k7f.cif.gz	445.4 KB	Display	PDBx/mmCIF format
PDB format	pdb3k7f.ent.gz	363.4 KB	Display	PDB format
PDBx/mmJSON format	3k7f.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/k7/3k7f ftp://data.pdbj.org/pub/pdb/validation_reports/k7/3k7f	HTTPS FTP

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Related structure data

Related structure data	3k83C 3k84C 2wj1S 2wj2 S: Starting model for refinement C: citing same article (ref.)
Similar structure data	3qkv-d 3lj7-d 2wap-d 3k84-d 2wj2-d 4do3-d 3lj6-d 3k83-d 3ppm-d 3qj8-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)	103.870, 103.870, 255.410
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: deltaTM-FAAH / 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 References: UniProt: P97612, Hydrolases; Acting on carbon-nitrogen bonds, other than peptide bonds; In linear amides
#2: Chemical	ChemComp-F2C / 6-[2-(7-phenylheptanoyl)-1,3-oxazol-5-yl]pyridine-2-carboxylic acid / 6-(2-(7-phenylheptanoyl)oxazol-5-yl)picolinate Mass: 378.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂₂H₂₂N₂O₄
#3: Chemical	ChemComp-CL / CHLORIDE ION Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical	ChemComp-NA / SODIUM ION Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 1100 / Source method: isolated from a natural source / Formula: H₂O
Has protein modification	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: 3.15 Å³/Da / Density % sol: 60.97 %
Crystal grow	Temperature: 287 K / Method: vapor diffusion, sitting drop / pH: 8.5 Details: 30% PEG400, 100mM TrisHCl, 100mM sodium chloride, 100mM lithium sulfate, pH 8.5, VAPOR DIFFUSION, SITTING DROP, temperature 287K

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Data collection

Diffraction	Mean temperature: 100 K
Diffraction source	Source: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.0331 Å
Detector	Type: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Oct 15, 2008
Radiation	Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 1.0331 Å / Relative weight: 1
Reflection	Resolution: 1.95→38.477 Å / Num. all: 117077 / Num. obs: 115337 / % possible obs: 98.5 % / Observed criterion σ(I): -3 / Redundancy: 5.5 % / R_merge(I) obs: 0.14 / Net I/σ(I): 9.2
Reflection shell	Resolution: 1.95→2.02 Å / Redundancy: 5.1 % / R_merge(I) obs: 0.68 / Mean I/σ(I) obs: 2 / % possible all: 97.7

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Processing

Software

Name	Version	Classification
XDS		data scaling
PHASER		phasing
PHENIX	(phenix.refine: 1.5_2)	refinement
XDS		data reduction
XSCALE		data scaling

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2WJ1

2wj1

Resolution: 1.95→38.477 Å / SU ML: 0.2 / σ(F): 1.99 / Phase error: 17.07 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection
R_free	0.1883	5770	5.04 %
R_work	0.1545	-	-
obs	0.1562	114378	97.72 %

Solvent computation

Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / B_sol: 38.02 Å² / k_sol: 0.329 e/Å³

Displacement parameters

B_iso mean: 23.7 Å²

Refinement step

Cycle: LAST / Resolution: 1.95→38.477 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	8431	0	58	1100	9589

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.011	8688
X-RAY DIFFRACTION	f_angle_d	1.254	11795
X-RAY DIFFRACTION	f_dihedral_angle_d	18.5	3246
X-RAY DIFFRACTION	f_chiral_restr	0.085	1315
X-RAY DIFFRACTION	f_plane_restr	0.006	1524

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 (%)
1.95-1.9722	0.2648	188	0.2271	3482	X-RAY DIFFRACTION	95
1.9722-1.9954	0.2446	177	0.2162	3583	X-RAY DIFFRACTION	97
1.9954-2.0197	0.2482	185	0.2053	3459	X-RAY DIFFRACTION	95
2.0197-2.0453	0.2267	175	0.1949	3582	X-RAY DIFFRACTION	97
2.0453-2.0722	0.2547	188	0.1974	3553	X-RAY DIFFRACTION	97
2.0722-2.1006	0.2484	194	0.1911	3548	X-RAY DIFFRACTION	97
2.1006-2.1306	0.2319	181	0.1812	3577	X-RAY DIFFRACTION	98
2.1306-2.1624	0.2161	190	0.173	3589	X-RAY DIFFRACTION	97
2.1624-2.1962	0.207	193	0.1699	3554	X-RAY DIFFRACTION	97
2.1962-2.2322	0.2265	205	0.169	3571	X-RAY DIFFRACTION	98
2.2322-2.2706	0.2199	193	0.1602	3594	X-RAY DIFFRACTION	98
2.2706-2.3119	0.1825	180	0.1557	3642	X-RAY DIFFRACTION	98
2.3119-2.3564	0.1966	195	0.1535	3610	X-RAY DIFFRACTION	99
2.3564-2.4045	0.2003	195	0.1508	3592	X-RAY DIFFRACTION	98
2.4045-2.4568	0.1873	225	0.1526	3596	X-RAY DIFFRACTION	98
2.4568-2.5139	0.1974	181	0.1503	3640	X-RAY DIFFRACTION	99
2.5139-2.5768	0.1892	184	0.1507	3636	X-RAY DIFFRACTION	98
2.5768-2.6464	0.2089	212	0.1531	3620	X-RAY DIFFRACTION	98
2.6464-2.7243	0.1816	196	0.1494	3655	X-RAY DIFFRACTION	99
2.7243-2.8122	0.1808	175	0.1493	3680	X-RAY DIFFRACTION	99
2.8122-2.9126	0.1835	198	0.1477	3610	X-RAY DIFFRACTION	99
2.9126-3.0292	0.1962	177	0.1542	3682	X-RAY DIFFRACTION	99
3.0292-3.167	0.1829	220	0.1447	3639	X-RAY DIFFRACTION	98
3.167-3.3339	0.1684	188	0.1471	3670	X-RAY DIFFRACTION	98
3.3339-3.5426	0.1696	193	0.1377	3656	X-RAY DIFFRACTION	98
3.5426-3.816	0.1477	193	0.1247	3693	X-RAY DIFFRACTION	98
3.816-4.1995	0.1536	198	0.1316	3642	X-RAY DIFFRACTION	97
4.1995-4.8062	0.1327	177	0.1192	3707	X-RAY DIFFRACTION	97
4.8062-6.0516	0.1726	211	0.1425	3720	X-RAY DIFFRACTION	97
6.0516-38.4849	0.1747	203	0.1658	3826	X-RAY DIFFRACTION	96

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	0.6077	0.0571	-0.2701	0.5852	-0.1521	0.4932	-0.0234	0.3533	-0.02	-0.4283	-0.0434	-0.2776	0.0828	0.119	0.0633	0.196	0.0186	0.069	0.3001	-0.0272	0.1197	-23.1716	33.8058	-14.2565
2	0.5551	-0.3874	-0.0094	1.315	0.3891	0.2248	-0.0221	0.1282	0.0004	-0.1859	0.0394	-0.2314	0.1854	0.1349	-0.0296	0.1544	0.0413	0.0439	0.219	-0.0518	0.1398	-24.9094	19.2218	-5.0266
3	0.3123	-0.2465	0.2344	1.329	-0.2554	0.2939	0.0796	0.2062	0.0406	-0.0322	-0.1487	-0.2266	-0.0299	0.2122	0.0682	0.0893	0.0037	0.0171	0.2098	0.0066	0.1327	-23.1718	36.9328	0.6327
4	0.275	-0.0606	-0.2053	0.4241	-0.1441	0.3844	0.0015	0.123	0.0001	-0.0685	0.0215	-0.0207	0.035	0.0611	-0.0218	0.0943	0.0045	-0.0049	0.1526	-0.0108	0.0739	-33.9853	33.6622	2.8539
5	0.6696	0.2468	0.4078	0.0147	0.1198	1.314	0.0181	0.1119	-0.005	0.0675	-0.0274	-0.0208	0.1737	0.1722	-0.0106	0.1277	0.0217	-0.0094	0.1356	-0.0299	0.1024	-29.4471	24.1978	14.3171
6	0.3868	0.2232	-0.0082	0.6484	-0.0642	0.754	0.0226	0.0609	0.0558	-0.0025	-0.0083	0.1198	0.0097	-0.129	-0.0063	0.0212	0.0032	-0.0139	0.1004	-0.0113	0.056	-48.4202	35.179	11.0563
7	0.7304	-0.3632	0.5144	0.5176	-0.353	0.8777	-0.021	-0.0925	0.0605	0.0134	-0.051	0.0424	-0.1781	-0.2535	0.0544	0.1108	0.0558	-0.0232	0.134	-0.0176	0.1232	-48.3922	54.8924	16.4055
8	0.4376	-0.0267	0.0863	0.4073	0.1558	0.7805	0.0074	0.0539	-0.0201	-0.0422	-0.0206	0.0506	0.0162	-0.0845	0.0159	0.0736	-0.0035	-0.0167	0.1281	-0.0083	0.072	-50.697	30.7798	8.9516
9	0.2857	0.1517	-0.3621	0.193	0.0122	0.8101	0.0201	-0.1118	0.0705	0.0889	-0.1589	-0.0683	0.0964	-0.0105	0.0932	0.1255	-0.0146	0.0211	0.2158	-0.0095	0.1161	-40.9348	38.3022	64.5513
10	0.6423	0.1899	-0.1239	1.1318	-0.2246	0.716	-0.0441	-0.1411	-0.0816	0.1629	0.0198	0.1156	0.1838	-0.051	0.0238	0.1221	-0.0279	0.0082	0.1236	0.029	0.1072	-34.0275	24.3798	58.0798
11	0.0107	0.1214	0.0532	1.2597	0.1802	0.5377	0.0293	-0.072	0.0497	0.0991	-0.0714	0.1336	0.0514	-0.0467	0.0419	0.0904	-0.0213	0.0108	0.1374	-0.0106	0.1228	-41.7919	38.8179	49.1058
12	0.1511	-0.102	-0.1004	0.2584	0.2325	0.3677	-0.0106	-0.0078	0.0349	-0.0033	0.0118	-0.0005	0.0058	0.0218	0.0014	0.0519	-0.0107	-0.0078	0.0966	-0.0035	0.0782	-30.4236	39.165	47.2153
13	0.3228	0.102	-0.2291	0.1853	0.15	0.5896	0.0302	-0.0264	-0.033	0.0358	-0.0484	-0.0036	0.1598	-0.0061	0.0224	0.1217	-0.0106	-0.006	0.1145	-0.0085	0.0863	-30.865	26.5489	38.0356
14	0.3929	-0.0558	0.0648	0.4503	0.0336	0.5114	-0.008	0.0573	0.0307	0.0091	0.0257	-0.0853	-0.0291	0.1505	-0.0152	0.0532	-0.0229	-0.0103	0.1143	0.0019	0.077	-17.3818	44.2253	38.2355
15	0.7443	-0.2138	0.4345	0.065	0.0917	0.3555	-0.1384	0.5449	0.2093	-0.1553	0.0307	0.0236	-0.3534	0.2407	0.0954	0.1178	-0.1089	-0.0451	-0.016	0.1261	0.0852	-24.3277	61.0069	28.8349
16	0.6992	0.0395	0.047	0.5699	0.1528	0.6082	-0.0064	0.0117	0.0022	-0.0023	0.0133	-0.0204	0.0134	0.1207	-0.0069	0.0331	-0.0002	-0.0114	0.11	-0.0032	0.0648	-13.7677	40.9868	41.3946

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details	Auth asym-ID	Auth seq-ID
1	X-RAY DIFFRACTION	1	(chain A and resid 32:70)	A	32 - 70
2	X-RAY DIFFRACTION	2	(chain A and resid 71:134)	A	71 - 134
3	X-RAY DIFFRACTION	3	(chain A and resid 135:165)	A	135 - 165
4	X-RAY DIFFRACTION	4	(chain A and resid 166:276)	A	166 - 276
5	X-RAY DIFFRACTION	5	(chain A and resid 277:315)	A	277 - 315
6	X-RAY DIFFRACTION	6	(chain A and resid 316:410)	A	316 - 410
7	X-RAY DIFFRACTION	7	(chain A and resid 411:451)	A	411 - 451
8	X-RAY DIFFRACTION	8	(chain A and resid 452:577)	A	452 - 577
9	X-RAY DIFFRACTION	9	(chain B and resid 32:70)	B	32 - 70
10	X-RAY DIFFRACTION	10	(chain B and resid 71:134)	B	71 - 134
11	X-RAY DIFFRACTION	11	(chain B and resid 135:165)	B	135 - 165
12	X-RAY DIFFRACTION	12	(chain B and resid 166:276)	B	166 - 276
13	X-RAY DIFFRACTION	13	(chain B and resid 277:315)	B	277 - 315
14	X-RAY DIFFRACTION	14	(chain B and resid 316:410)	B	316 - 410
15	X-RAY DIFFRACTION	15	(chain B and resid 411:451)	B	411 - 451
16	X-RAY DIFFRACTION	16	(chain B and resid 452:577)	B	452 - 577

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