PDB-3k83: Crystal Structure Analysis of a Biphenyl/Oxazole/Carboxypyridine ...

ID or keywords:

Entry

Database: PDB / ID: 3k83

Title

Crystal Structure Analysis of a Biphenyl/Oxazole/Carboxypyridine alpha-ketoheterocycle Inhibitor Bound to a Humanized Variant of Fatty Acid Amide Hydrolase

Components

Fatty-acid amide hydrolase 1

Keywords

HYDROLASE / faah / oxazole / conjugate / covalent modification / Membrane / Transmembrane / monotopic / fatty acid / serine hydrolase / endocannabinoid / reversible inhibitor.

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: 2.251 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	Nov 6, 2024	Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	3k83.cif.gz	440.7 KB	Display	PDBx/mmCIF format
PDB format	pdb3k83.ent.gz	358.1 KB	Display	PDB format
PDBx/mmJSON format	3k83.json.gz		Tree view	PDBx/mmJSON format
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Validation report

Summary document	3k83_validation.pdf.gz	947 KB	Display	wwPDB validaton report
Full document	3k83_full_validation.pdf.gz	954.4 KB	Display
Data in XML	3k83_validation.xml.gz	46.4 KB	Display
Data in CIF	3k83_validation.cif.gz	69.5 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/k8/3k83 ftp://data.pdbj.org/pub/pdb/validation_reports/k8/3k83	HTTPS FTP

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Related structure data

Related structure data	3k7fC 3k84C 2wj1S 2wj2 S: Starting model for refinement C: citing same article (ref.)
Similar structure data	3k84-d 3lj6-d 3ppm-d 4do3-d 1mt5-5 2vya-d 2wap-d 2wj2-d 3lj7-d 3pr0-d 3k7f-d 3qj9-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)	103.404, 103.404, 254.439
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-F27 / 6-[2-(3-biphenyl-4-ylpropanoyl)-1,3-oxazol-5-yl]pyridine-2-carboxylic acid / 6-(2-(3-(biphenyl-4-yl)propanoyl)oxazol-5-yl)picolinate Mass: 398.411 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂₄H₁₈N₂O₄
#3: Chemical	ChemComp-CL / CHLORIDE ION Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical	ChemComp-1DO / 1-DODECANOL Mass: 186.334 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₁₂H₂₆O
#5: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 794 / 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: 3.11 Å³/Da / Density % sol: 60.46 %
Crystal grow	Temperature: 287 K / Method: vapor diffusion, sitting drop / pH: 7.5 Details: 30% PEG400, 100mM Hepes, 100mM NaCl , pH 7.5, VAPOR DIFFUSION, SITTING DROP, temperature 287.0K

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Data collection

Diffraction	Mean temperature: 100 K
Diffraction source	Source: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.03312 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: 1.03312 Å / Relative weight: 1
Reflection	Resolution: 2.2→30 Å / Num. all: 78344 / Num. obs: 75832 / % possible obs: 93.9 % / Redundancy: 4.5 % / R_merge(I) obs: 0.151 / Net I/σ(I): 7.8
Reflection shell	Resolution: 2.2→2.28 Å / Redundancy: 3.5 % / R_merge(I) obs: 0.497 / Mean I/σ(I) obs: 2.5 / % possible all: 92.1

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Processing

Software

Name	Version	Classification
HKL-2000		data collection
PHASER		phasing
PHENIX	(phenix.refine)	refinement
HKL-2000		data reduction
HKL-2000		data scaling

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 2wj1

2wj1

Resolution: 2.251→29.88 Å / SU ML: 0.26 / Isotropic thermal model: isotropic + 16-group TLS / σ(F): 1.89 / Phase error: 18.15 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection
R_free	0.1983	3587	5.07 %
R_work	0.1439	-	-
obs	0.1466	70775	93.71 %

Solvent computation

Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / B_sol: 36.404 Å² / k_sol: 0.342 e/Å³

Displacement parameters

B_iso mean: 26.4 Å²

Refinement step

Cycle: LAST / Resolution: 2.251→29.88 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	8457	0	74	794	9325

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.012	8733
X-RAY DIFFRACTION	f_angle_d	1.306	11854
X-RAY DIFFRACTION	f_dihedral_angle_d	19.7	3254
X-RAY DIFFRACTION	f_chiral_restr	0.085	1317
X-RAY DIFFRACTION	f_plane_restr	0.006	1532

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 (%)
2.2511-2.2807	0.2568	134	0.1765	2459	X-RAY DIFFRACTION	92
2.2807-2.3119	0.2262	115	0.1709	2567	X-RAY DIFFRACTION	93
2.3119-2.345	0.2463	147	0.162	2539	X-RAY DIFFRACTION	94
2.345-2.38	0.2192	139	0.1567	2530	X-RAY DIFFRACTION	94
2.38-2.4171	0.2119	139	0.1578	2561	X-RAY DIFFRACTION	94
2.4171-2.4567	0.2429	151	0.1608	2592	X-RAY DIFFRACTION	95
2.4567-2.4991	0.2392	125	0.1562	2571	X-RAY DIFFRACTION	94
2.4991-2.5445	0.2402	131	0.1563	2592	X-RAY DIFFRACTION	95
2.5445-2.5934	0.2179	147	0.1467	2634	X-RAY DIFFRACTION	95
2.5934-2.6463	0.21	138	0.1436	2592	X-RAY DIFFRACTION	95
2.6463-2.7038	0.199	149	0.1405	2587	X-RAY DIFFRACTION	95
2.7038-2.7667	0.2217	138	0.1427	2605	X-RAY DIFFRACTION	95
2.7667-2.8358	0.2078	132	0.1488	2599	X-RAY DIFFRACTION	95
2.8358-2.9124	0.2194	154	0.1448	2587	X-RAY DIFFRACTION	95
2.9124-2.998	0.2205	130	0.1525	2599	X-RAY DIFFRACTION	95
2.998-3.0947	0.1932	157	0.1461	2599	X-RAY DIFFRACTION	95
3.0947-3.2052	0.2162	141	0.1455	2601	X-RAY DIFFRACTION	94
3.2052-3.3334	0.1912	133	0.1447	2612	X-RAY DIFFRACTION	94
3.3334-3.4849	0.1776	137	0.137	2578	X-RAY DIFFRACTION	94
3.4849-3.6683	0.1806	147	0.1306	2585	X-RAY DIFFRACTION	94
3.6683-3.8977	0.1686	113	0.1221	2622	X-RAY DIFFRACTION	93
3.8977-4.1979	0.1764	143	0.1259	2563	X-RAY DIFFRACTION	93
4.1979-4.6189	0.1545	127	0.1175	2601	X-RAY DIFFRACTION	92
4.6189-5.2841	0.1644	151	0.1148	2571	X-RAY DIFFRACTION	92
5.2841-6.6453	0.1978	136	0.1456	2583	X-RAY DIFFRACTION	91
6.6453-29.8828	0.1493	133	0.1419	2659	X-RAY DIFFRACTION	89

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	0.3116	0.0655	0.0027	0.2418	-0.0048	0.0024	-0.0821	-0.2006	0.0449	0.3115	-0.0063	0.037	0.0779	-0.037	0.0617	0.2689	0.0121	0.066	0.1873	-0.0491	0.0752	40.0024	-3.2704	14.3515
2	0.7293	-0.1903	-0.8198	0.3537	0.1916	0.9172	-0.026	0.0431	-0.0139	0.1167	-0.0204	0.0636	-0.0034	-0.1762	0.0329	0.0995	0.0214	0.0336	0.1271	0.0009	0.0839	28.9414	-11.843	5.1329
3	1.8186	-0.4795	0.6887	0.1871	-0.0842	0.4241	-0.15	-0.0931	0.0719	-0.0172	0.0516	-0.0763	-0.1662	-0.0661	0.0988	0.1095	0.0402	0.0026	0.0744	-0.0019	0.0645	43.3633	-1.5021	-0.5936
4	0.1439	-0.0353	0.0326	0.2233	0.0374	0.0146	-0.0052	-0.0431	0.031	0.1179	0.0354	0.0188	-0.0255	-0.033	-0.0224	0.037	0.0196	-0.0015	0.025	0.0056	-0.0038	45.944	-12.4811	-2.7943
5	0.1242	-0.1162	0.097	0.1937	-0.2731	0.6029	-0.0767	0.0144	-0.002	0.0349	0.0826	0.0377	-0.0587	-0.1838	-0.0217	0.0562	0.0146	0.0062	0.1084	0.013	0.0545	35.4549	-13.3076	-14.1926
6	0.198	0.0179	0.0018	0.0287	-0.1081	0.5754	-0.0269	-0.034	-0.0475	-0.0138	0.0175	-0.0207	0.0564	0.0402	0.0171	0.0589	0.032	0.0013	0.0262	0.0141	0.0302	54.5094	-24.21	-10.9975
7	0.0211	-0.1581	0.0486	1.1675	-0.419	0.3835	-0.0266	0.0394	0.032	-0.0764	-0.0845	-0.1834	0.0642	0.2746	0.1141	0.0595	0.0275	0.0049	0.179	0.0366	0.0915	71.4442	-14.3107	-16.444
8	0.3371	-0.0323	-0.0148	0.2339	-0.0415	0.0026	-0.035	0.0427	-0.0292	-0.0159	0.0194	-0.0033	0.0603	-0.0006	0.0157	0.092	0.0175	-0.0019	0.0684	0.0123	0.0247	51.2706	-28.5303	-8.6577
9	0.7194	0.005	-0.3964	0.1526	-0.0352	0.2338	-0.0214	-0.072	0.0153	-0.1514	-0.0846	0.0033	0.113	-0.0836	0.0922	0.1603	0.0284	0.0143	0.1213	-0.0236	0.0734	53.3002	-16.1564	-64.3902
10	0.6633	0.5528	0.4612	0.4877	0.4364	0.5118	-0.0107	0.0811	-0.0784	-0.0597	-0.0299	-0.0288	0.0844	-0.0676	0.0227	0.1022	-0.0121	-0.0122	0.0636	-0.0245	0.0515	37.8011	-17.0814	-57.9001
11	1.1139	0.0021	-0.045	0.0012	-0.0229	0.2328	-0.0297	0.019	-0.1059	-0.0083	0.0427	0.002	0.143	0.0245	-0.0049	0.0805	0.0041	0.0009	0.0288	-0.006	0.062	54.2069	-16.6174	-48.9676
12	0.1355	0.0134	-0.114	0.0079	0.0377	0.2942	-0.0233	0.0555	-0.064	-0.0281	-0.0536	-0.0169	0.0943	-0.0871	0.015	0.0316	0.0283	-0.0158	-0.0491	0.0609	-0.0238	48.8226	-6.6371	-47.0651
13	0.1734	0.0396	0.4336	0.6226	-0.5736	1.8307	-0.0936	-0.0661	0.0057	-0.1277	0.0513	-0.0267	0.0833	-0.2925	0.0293	0.056	-0.0024	0.0186	0.0742	0.0009	0.0258	38.0987	-13.318	-37.8989
14	0.6356	-0.0747	0.1738	0.0467	-0.1306	0.2659	-0.0249	0.0193	0.0774	0.0072	0.0748	-0.056	-0.2076	0.0944	0.0215	-0	0.0688	-0.0414	-0.091	0.0335	-0.0014	46.7148	7.1327	-38.0842
15	0.1627	0.0406	0.1473	0.0107	0.0399	0.2704	-0.0305	-0.0128	0.0143	0.0819	0.0148	-0.0237	-0.1287	0.0443	0.045	0.1015	-0.0252	-0.0618	0.0462	0.0092	0.0723	64.7042	9.4621	-28.7542
16	0.0765	-0.1095	0.0503	0.3224	-0.0752	0.1587	-0.0098	-0.0062	0.0103	0.0217	0.0178	0.0115	-0.0826	-0.0376	-0.0009	0.0515	0.0176	-0.0004	0.0248	0.0119	0.021	42.0992	8.6476	-41.2148

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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