PDB-3k84: Crystal Structure Analysis of a Oleyl/Oxadiazole/pyridine Inhibit...

ID or keywords:

Entry

Database: PDB / ID: 3k84

Title

Crystal Structure Analysis of a Oleyl/Oxadiazole/pyridine 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 / oxadiazole / alpha-ketoheterocycle / 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: 2.25 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	3k84.cif.gz	437.6 KB	Display	PDBx/mmCIF format
PDB format	pdb3k84.ent.gz	357.4 KB	Display	PDB format
PDBx/mmJSON format	3k84.json.gz		Tree view	PDBx/mmJSON format
Others	Other downloads

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Validation report

Summary document	3k84_validation.pdf.gz	837.1 KB	Display	wwPDB validaton report
Full document	3k84_full_validation.pdf.gz	841.5 KB	Display
Data in XML	3k84_validation.xml.gz	44.7 KB	Display
Data in CIF	3k84_validation.cif.gz	66.5 KB	Display
Arichive directory	https://data.pdbj.org/pub/pdb/validation_reports/k8/3k84 ftp://data.pdbj.org/pub/pdb/validation_reports/k8/3k84	HTTPS FTP

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Related structure data

Related structure data	3k7fC 3k83C 2wj1S 2wj2 S: Starting model for refinement C: citing same article (ref.)
Similar structure data	3k83-d 3lj6-d 3qkv-d 2wj1-d 3qj9-d 3k7f-d 3ppm-d 2vya-d 3lj7-d 4hbp-d 2wap-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)	104.050, 104.050, 255.320
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-K84 / (9Z)-1-(5-pyridin-2-yl-1,3,4-oxadiazol-2-yl)octadec-9-en-1-one Mass: 411.580 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂₅H₃₇N₃O₂
#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.: 684 / 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: 3.16 Å³/Da / Density % sol: 61.09 %
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: SSRL / Beamline: BL11-1 / Wavelength: 0.97945 Å
Detector	Type: MARMOSAIC 325 mm CCD / Detector: CCD / Date: Mar 25, 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: 2.25→30 Å / Num. all: 7 / Num. obs: 76742 / % possible obs: 99.8 % / Redundancy: 4.6 % / R_merge(I) obs: 0.11 / Net I/σ(I): 12.2
Reflection shell	Resolution: 2.25→2.32 Å / Redundancy: 4.5 % / R_merge(I) obs: 0.689 / Mean I/σ(I) obs: 2.1 / % possible all: 99.7

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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: 2wj1

2wj1

Resolution: 2.25→28.334 Å / SU ML: 0.28 / Isotropic thermal model: isotropic + 16-group TLS / σ(F): 1.99 / Phase error: 19.1 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection
R_free	0.2106	3871	5.04 %
R_work	0.1662	-	-
obs	0.1684	76735	99.83 %

Solvent computation

Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / B_sol: 36.372 Å² / k_sol: 0.333 e/Å³

Displacement parameters

B_iso mean: 30.6 Å²

Refinement step

Cycle: LAST / Resolution: 2.25→28.334 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	8429	0	61	684	9174

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.01	8686
X-RAY DIFFRACTION	f_angle_d	1.213	11783
X-RAY DIFFRACTION	f_dihedral_angle_d	19.105	3251
X-RAY DIFFRACTION	f_chiral_restr	0.071	1314
X-RAY DIFFRACTION	f_plane_restr	0.004	1522

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 (%)
2.25-2.2774	0.3335	146	0.2508	2571	X-RAY DIFFRACTION	100
2.2774-2.3063	0.2914	158	0.226	2547	X-RAY DIFFRACTION	100
2.3063-2.3366	0.252	127	0.2066	2591	X-RAY DIFFRACTION	100
2.3366-2.3686	0.2832	126	0.2011	2570	X-RAY DIFFRACTION	100
2.3686-2.4024	0.2788	132	0.1993	2580	X-RAY DIFFRACTION	100
2.4024-2.4382	0.2465	132	0.1879	2569	X-RAY DIFFRACTION	100
2.4382-2.4763	0.2265	131	0.185	2583	X-RAY DIFFRACTION	100
2.4763-2.5169	0.2549	139	0.185	2542	X-RAY DIFFRACTION	100
2.5169-2.5603	0.2295	126	0.1896	2561	X-RAY DIFFRACTION	100
2.5603-2.6068	0.2349	135	0.1758	2644	X-RAY DIFFRACTION	100
2.6068-2.6569	0.2451	140	0.1796	2565	X-RAY DIFFRACTION	100
2.6569-2.7111	0.2359	120	0.1747	2566	X-RAY DIFFRACTION	100
2.7111-2.77	0.2442	141	0.1705	2585	X-RAY DIFFRACTION	100
2.77-2.8344	0.2309	146	0.1723	2588	X-RAY DIFFRACTION	100
2.8344-2.9052	0.2249	139	0.1702	2603	X-RAY DIFFRACTION	100
2.9052-2.9836	0.2308	144	0.1722	2573	X-RAY DIFFRACTION	100
2.9836-3.0713	0.2158	122	0.1686	2601	X-RAY DIFFRACTION	100
3.0713-3.1704	0.2	141	0.1603	2589	X-RAY DIFFRACTION	100
3.1704-3.2835	0.2029	129	0.1582	2611	X-RAY DIFFRACTION	100
3.2835-3.4148	0.1858	159	0.1576	2574	X-RAY DIFFRACTION	100
3.4148-3.5699	0.184	150	0.1456	2607	X-RAY DIFFRACTION	100
3.5699-3.7577	0.1853	159	0.1442	2597	X-RAY DIFFRACTION	100
3.7577-3.9925	0.1854	131	0.1419	2641	X-RAY DIFFRACTION	100
3.9925-4.2998	0.1842	145	0.1409	2616	X-RAY DIFFRACTION	100
4.2998-4.7307	0.1443	134	0.1321	2669	X-RAY DIFFRACTION	100
4.7307-5.4111	0.1773	145	0.1434	2621	X-RAY DIFFRACTION	100
5.4111-6.8019	0.1883	140	0.1708	2682	X-RAY DIFFRACTION	100
6.8019-28.3365	0.1919	134	0.1729	2818	X-RAY DIFFRACTION	99

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	1.1382	-0.1229	0.5621	0.479	0.1088	0.4549	-0.1582	-0.0726	-0.054	0.3199	-0.0621	-0.0096	-0.0074	-0.0987	0.1571	0.2616	-0.0723	-0.0269	0.1564	-0.0241	0.1239	-50.1795	16.3691	21.8702
2	1.7199	-0.8059	0.1156	0.6683	0.1042	0.5983	0.0273	-0.1402	0.2322	0.1372	-0.0328	-0.0638	-0.138	-0.0686	-0.014	0.2109	-0.0247	0.0498	0.1176	-0.0212	0.1555	-65.681	17.308	15.5003
3	0.6759	-0.3445	0.0126	0.1795	-0.0016	0.2512	-0.0887	0.0618	0.2081	0.0666	0.042	-0.0991	-0.2011	0.0224	0.0446	0.2158	-0.047	-0.0047	0.1299	-0.0038	0.186	-49.3321	16.7562	6.4581
4	0.2858	-0.2074	0.0849	0.1712	-0.0132	0.1478	0.0321	-0.0012	0.0423	0.0111	-0.0371	-0.0863	0.0003	-0.0269	0.0005	0.1821	-0.0401	-0.0045	0.1005	0.0029	0.1387	-54.746	6.7609	4.6387
5	0.2174	0.1004	0.1447	0.426	-0.4153	0.6858	-0.0476	0.0732	0.0476	0.0473	0.0402	0.0784	-0.1417	-0.0745	0.0161	0.2121	-0.0145	0.0092	0.1589	0.0153	0.1428	-65.4422	13.4584	-4.5227
6	0.6206	-0.0377	0.0769	0.403	-0.0555	0.688	-0.0092	0.012	-0.1208	-0.0549	-0.0018	0.0039	0.1689	-0.0089	0.0252	0.1529	-0.048	0.0168	0.0384	0.0076	0.1228	-56.8848	-7.0949	-4.3136
7	1.5865	-0.911	0.0427	1.1788	-0.6	0.7254	-0.0124	0.223	-0.1939	-0.4906	-0.0648	-0.0723	0.4225	0.221	0.1063	0.2635	0.0276	0.094	0.1438	-0.0041	0.2043	-38.7263	-9.7158	-13.6595
8	0.4076	0.2481	-0.0659	0.8289	0.0494	0.3102	-0.0155	0.0104	-0.051	-0.0282	0.0045	0.01	0.1057	-0.0504	0.0178	0.1512	-0.0665	0.0029	0.0827	0.0087	0.1086	-61.4914	-8.538	-1.1569
9	1.2	0.0811	-0.3099	0.6197	0.3957	0.4728	-0.1711	0.5117	-0.3223	-0.4785	0.0698	0.0864	-0.0312	-0.145	0.106	0.3905	-0.0298	-0.073	0.3531	-0.0529	0.1932	-63.1306	3.3189	-56.7902
10	1.1458	-0.422	0.6902	1.3004	0.4456	1.0193	0.0866	0.2286	-0.1704	-0.278	-0.1464	0.2631	-0.0296	-0.3468	0.0644	0.207	-0.0258	-0.0734	0.2871	-0.0099	0.1999	-74.9143	12.1813	-47.5514
11	2.7589	-0.0554	-0.9226	0.3487	0.4794	0.9154	-0.2599	0.2753	-0.2723	0.1932	0.1168	-0.0222	0.3904	-0.1432	0.1551	0.2875	-0.0612	0.014	0.204	-0.0248	0.1896	-60.4168	1.782	-41.9371
12	0.5535	-0.0681	-0.3017	0.4541	0.2426	0.2606	0.0241	0.1129	-0.0372	-0.1714	0.0235	-0.0057	0.0187	-0.042	-0.0419	0.1864	-0.0306	-0.0111	0.138	-0.0087	0.1018	-57.9654	12.8745	-39.8206
13	0.2033	0.2408	-0.2173	0.3759	-0.0462	1.8083	-0.1353	0.0384	-0.0423	-0.0848	0.0616	0.0378	0.154	-0.3884	0.0221	0.1643	-0.0117	-0.0338	0.2252	0.0407	0.1436	-68.2617	13.5238	-28.207
14	0.6936	-0.1543	-0.0478	0.4072	-0.1533	0.9087	0.0006	0.0733	0.1514	-0.0175	0.0009	-0.06	-0.1471	0.04	0.0026	0.1609	-0.0544	-0.009	0.0951	0.0216	0.1182	-49.2453	24.4465	-31.5228
15	0.1644	0.2336	-0.3677	1.0116	-0.4317	1.1907	-0.0176	-0.2074	-0.0083	0.1076	-0.0338	-0.1388	-0.0599	0.4231	0.058	0.1298	-0.0496	0.0056	0.2237	0.0192	0.1801	-32.2425	14.5266	-26.0414
16	0.6926	0.0952	-0.0598	0.5368	0.0881	0.5367	0.0133	0.0364	0.0974	0.0022	-0.0026	-0.0511	-0.1206	-0.0192	-0.0167	0.1265	-0.0292	0.0061	0.0783	0.0265	0.0685	-51.8977	28.56	-33.8202

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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