PDB-3pr0: Crystal Structure of a Covalently Bound alpha-Ketoheterocycle Inh...

ID or keywords:

Entry

Database: PDB / ID: 3pr0

Title

Crystal Structure of a Covalently Bound alpha-Ketoheterocycle Inhibitor (Phenhexyl/Oxadiazole/Pyridine) to a Humanized Variant of Fatty Acid Amide Hydrolase

Components

Fatty Acid Amide Hydrolase 1

Keywords

HYDROLASE/HYDROLASE INHIBITOR / protein-inhibitor complex / FAAH / oxadiazole / alpha-ketoheterocycle / endocannabinoid degradation / membrane protein / HYDROLASE-HYDROLASE INHIBITOR complex

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: 2.2 Å

Authors

Mileni, M. / Han, G.W. / Boger, D.L. / Stevens, R.C.

Citation

Journal: J.Am.Chem.Soc. / Year: 2011
Title: Fluoride-mediated capture of a noncovalent bound state of a reversible covalent enzyme inhibitor: X-ray crystallographic analysis of an exceptionally potent alpha-ketoheterocycle inhibitor of ...
Authors: Mileni, M. / Garfunkle, J. / Ezzili, C. / Cravatt, B.F. / Stevens, R.C. / Boger, D.L.

History

Deposition	Nov 29, 2010	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Nov 16, 2011	Provider: repository / Type: Initial release
Revision 1.1	Sep 6, 2023	Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_label_asym_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 1.2	Nov 6, 2024	Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	3pr0.cif.gz	443.8 KB	Display	PDBx/mmCIF format
PDB format	pdb3pr0.ent.gz	363.6 KB	Display	PDB format
PDBx/mmJSON format	3pr0.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/pr/3pr0 ftp://data.pdbj.org/pub/pdb/validation_reports/pr/3pr0	HTTPS FTP

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Related structure data

Related structure data	3ppmC 2wj1S 2wj2 3k7f 3k83 3k84 S: Starting model for refinement C: citing same article (ref.)
Similar structure data	3qj9-d 1mt5-4 3ppm-d 2vya-d 1mt5-1 3oj8-d 3qk5-d 3lj7-d 4hbp-d 1mt5-6 1mt5-3 3k83-d 1mt5-5 1mt5-7 3qkv-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)	102.240, 105.470, 149.150
Angle α, β, γ (deg.)	90.00, 90.00, 90.00
Int Tables number	19
Space group name H-M	P2₁2₁2₁

#1: Protein	Fatty Acid Amide Hydrolase 1 / Anandamide amidohydrolase 1 / Oleamide hydrolase 1 Mass: 63111.664 Da / Num. of mol.: 2 / Fragment: deltaTM-FAAH, 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, amidase
#2: Chemical	ChemComp-JG2 / 7-phenyl-1-[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]heptane-1,1-diol / 7-phenyl-1-[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]heptan-1-one, bound form Mass: 353.415 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂₀H₂₃N₃O₃
#3: Chemical	ChemComp-CL / CHLORIDE ION Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical	ChemComp-PEG / DI(HYDROXYETHYL)ETHER Mass: 106.120 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₄H₁₀O₃
#5: Water	ChemComp-HOH / water Mass: 18.015 Da / Num. of mol.: 579 / Source method: isolated from a natural source / Formula: H₂O
Has protein modification	Y
Nonpolymer details	THE STARTING MATERIAL IS 7-PHENYL-1-[5-(PYRIDIN-2-YL)-1,3,4-OXADIAZOL-2-YL]HEPTAN-1-ONE. IT BINDS ...THE STARTING MATERIAL IS 7-PHENYL-1-[5-(PYRIDIN-2-YL)-1,3,4-OXADIAZOL-2-YL]HEPTAN-1-ONE. IT BINDS COVALENTLY TO OG OF SER 241. JG2 CORRESPONDS TO THE FINAL PRODUCT.

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Experiment

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

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Sample preparation

Crystal	Density Matthews: 3.19 Å³/Da / Density % sol: 61.39 %
Crystal grow	Temperature: 287 K / Method: vapor diffusion / pH: 7.5 Details: 30% PEG400, 100 mM Hepes pH 7.5, 100 mM NaCl, VAPOR DIFFUSION, temperature 287K

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Data collection

Diffraction	Mean temperature: 100 K
Diffraction source	Source: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.0332 Å
Detector	Type: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Feb 7, 2009 / Details: mirrors
Radiation	Monochromator: Double crystal cryo-cooled / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 1.0332 Å / Relative weight: 1
Reflection	Resolution: 2.2→30 Å / Num. all: 82454 / Num. obs: 82372 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 5.2 % / B_iso Wilson estimate: 36.4 Å² / R_sym value: 0.088 / Net I/σ(I): 11.8
Reflection shell	Resolution: 2.2→2.26 Å / Redundancy: 5 % / Mean I/σ(I) obs: 2.4 / Num. unique all: 6339 / R_sym value: 0.671 / % possible all: 99.9

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Processing

Software

Name	Version	Classification
XDS		data scaling
PHASER		phasing
PHENIX	(phenix.refine: 1.6.4_486)	refinement
XDS		data reduction
XSCALE		data scaling

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: 2wj1

2wj1

Resolution: 2.2→29.739 Å / SU ML: 0.26
Isotropic thermal model: Isotropic with 16 groups TLS (8 each monomer)
Cross valid method: THROUGHOUT / σ(F): 2 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection	Selection details
R_free	0.1898	4106	4.99 %	Set copied from 2wj1
R_work	0.1501	-	-	-
obs	0.1521	82349	99.9 %	-
all	-	82398	-	-

Solvent computation

Shrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / B_sol: 42.269 Å² / k_sol: 0.325 e/Å³

Displacement parameters

B_iso mean: 40.4 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	2.9482 Å²	0 Å²	-0 Å²
2-	-	0.0558 Å²	-0 Å²
3-	-	-	-3.004 Å²

Refinement step

Cycle: LAST / Resolution: 2.2→29.739 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	8433	0	65	579	9077

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.007	8776
X-RAY DIFFRACTION	f_angle_d	1.063	11919
X-RAY DIFFRACTION	f_dihedral_angle_d	13.15	3319
X-RAY DIFFRACTION	f_chiral_restr	0.07	1329
X-RAY DIFFRACTION	f_plane_restr	0.004	1542

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 (%)
2.2-2.2259	0.252	127	0.2168	2716	X-RAY DIFFRACTION	100
2.2259-2.253	0.2701	111	0.2462	2655	X-RAY DIFFRACTION	100
2.253-2.2815	0.2497	125	0.21	2677	X-RAY DIFFRACTION	100
2.2815-2.3115	0.2327	144	0.2027	2649	X-RAY DIFFRACTION	100
2.3115-2.3432	0.2484	155	0.1868	2691	X-RAY DIFFRACTION	100
2.3432-2.3766	0.2435	137	0.1838	2655	X-RAY DIFFRACTION	100
2.3766-2.4121	0.2529	138	0.1802	2679	X-RAY DIFFRACTION	100
2.4121-2.4498	0.2124	157	0.1723	2633	X-RAY DIFFRACTION	100
2.4498-2.4899	0.2267	142	0.1689	2686	X-RAY DIFFRACTION	100
2.4899-2.5328	0.2292	141	0.1765	2681	X-RAY DIFFRACTION	100
2.5328-2.5789	0.2352	127	0.1613	2683	X-RAY DIFFRACTION	100
2.5789-2.6284	0.2138	132	0.1671	2664	X-RAY DIFFRACTION	100
2.6284-2.6821	0.2252	141	0.169	2683	X-RAY DIFFRACTION	100
2.6821-2.7403	0.2401	145	0.1627	2667	X-RAY DIFFRACTION	100
2.7403-2.804	0.2111	145	0.1584	2674	X-RAY DIFFRACTION	100
2.804-2.8741	0.2427	125	0.1621	2727	X-RAY DIFFRACTION	100
2.8741-2.9517	0.1885	128	0.1669	2679	X-RAY DIFFRACTION	100
2.9517-3.0385	0.2316	163	0.162	2680	X-RAY DIFFRACTION	100
3.0385-3.1365	0.19	146	0.1604	2678	X-RAY DIFFRACTION	100
3.1365-3.2485	0.2222	142	0.1537	2701	X-RAY DIFFRACTION	100
3.2485-3.3784	0.1857	145	0.1581	2688	X-RAY DIFFRACTION	100
3.3784-3.5319	0.1902	149	0.1506	2706	X-RAY DIFFRACTION	100
3.5319-3.7178	0.1682	147	0.1416	2713	X-RAY DIFFRACTION	100
3.7178-3.9502	0.1735	160	0.1351	2709	X-RAY DIFFRACTION	100
3.9502-4.2544	0.1519	155	0.1274	2691	X-RAY DIFFRACTION	100
4.2544-4.681	0.1623	151	0.1159	2739	X-RAY DIFFRACTION	100
4.681-5.355	0.1601	143	0.12	2762	X-RAY DIFFRACTION	100
5.355-6.7338	0.1648	153	0.1469	2777	X-RAY DIFFRACTION	100
6.7338-29.7417	0.1429	132	0.1266	2900	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	0.3787	0.519	-1.0289	1.1207	-1.2444	2.877	0.0418	-0.335	-0.2817	0.205	0.0002	0.1627	0.1847	0.0853	0.0497	0.274	0.0283	0.084	0.4348	0.0751	0.2119	-18.5972	24.7274	17.3727
2	1.5526	-0.2734	0.4187	0.8102	-0.3041	0.4381	-0.0214	-0.5942	-0.0953	0.2886	0.0112	-0.0614	-0.0067	0.2454	0.0532	0.275	0.0713	0.0251	0.4914	0.0778	0.1976	-2.0758	27.0275	16.5884
3	0.7639	-0.2717	-0.61	0.8233	-0.3159	0.8708	-0.1981	-0.0139	-0.221	0.0359	0.1292	0.2077	0.1241	-0.0234	0.0649	0.2455	0.0191	0.041	0.2918	0.0282	0.2708	-14.211	24.8638	2.3744
4	1.2281	-0.1035	-0.1775	0.4724	-0.3783	0.3964	0.0081	-0.2141	-0.0253	0.0819	0.0304	0.024	-0.0332	0.0106	-0.0325	0.1765	0.0227	0.0408	0.2314	0.0128	0.1408	-10.4219	35.9477	2.4679
5	0.5683	0.174	-0.1872	0.7885	-0.4336	0.3169	-0.0155	-0.1627	-0.0194	0.14	-0.046	-0.0438	-0.0456	0.1689	0.0467	0.2485	0.0229	0.0191	0.3296	0.0113	0.206	3.4828	31.6868	-2.6026
6	1.7432	0.4562	-0.0091	0.6526	-0.1077	1.1996	-0.0236	-0.0853	0.1177	0.0478	0.072	0.0498	-0.2964	-0.0284	-0.0346	0.2904	0.0395	0.0275	0.1672	-0.0115	0.2469	-7.9884	50.485	-5.3868
7	1.9546	-0.6647	-0.1925	0.3008	0.1855	0.9548	0.0749	0.1894	0.3465	-0.1809	0.0426	-0.0409	-0.3661	-0.1594	-0.0823	0.2866	0.0806	0.0001	0.1923	0.0471	0.2656	-21.9143	50.2049	-20.3106
8	1.3773	-0.0646	-0.1816	0.6539	-0.3242	1.1117	0.0144	-0.1787	0.1803	0.1344	0.0232	0.0013	-0.3146	0.0878	-0.0537	0.2869	-0.0055	0.0331	0.1777	-0.0513	0.1784	-4.8396	52.5491	-1.0635
9	2.5485	0.8613	-0.2646	0.6414	0.2514	0.662	-0.2544	0.6257	0.4804	-0.5205	0.0569	-0.1094	-0.2965	0.2874	0.1217	0.5112	-0.1028	0.0867	0.4608	0.1368	0.2973	15.053	43.3403	-53.343
10	0.9721	0.3869	-0.6038	0.987	-0.217	0.8769	0.0009	0.1219	0.0765	-0.1693	-0.0346	-0.1561	-0.1201	0.4096	0.038	0.2976	-0.0704	0.0439	0.361	0.022	0.2671	25.2109	36.4141	-40.8774
11	2.9818	0.6227	0.9351	0.3844	0.6599	1.1564	-0.0728	0.1876	0.4587	-0.3229	-0.0178	0.1111	-0.4546	0.1578	0.09	0.3967	-0.0171	0.0169	0.2331	0.0295	0.303	8.176	43.9875	-40.1914
12	0.7008	0.1411	0.1568	0.2384	-0.138	0.6015	0.0012	0.0715	0.0873	-0.1066	0.035	0.0052	-0.1032	0.0328	-0.0294	0.2608	-0.0023	0.0175	0.1949	0.0089	0.1809	7.2214	32.4577	-38.7263
13	0.1611	0.0157	-0.3741	0.1404	0.0795	0.9579	0.0135	-0.0363	-0.022	-0.0153	-0.0045	0.0133	0.0063	0.2244	-0.0059	0.1839	-0.0053	0.0324	0.2589	-0.0057	0.1712	13.4491	33.3654	-24.3383
14	0.636	-0.4635	-0.1444	0.7817	-0.063	1.3264	-0.0241	0.0353	-0.1274	0.0038	-0.0262	0.1144	0.1149	-0.0129	0.0311	0.2174	-0.0021	-0.0036	0.1478	0.0037	0.2429	-1.3059	19.2427	-33.3439
15	0.0186	-0.0518	-0.1493	1.2258	1.3284	1.9728	-0.01	-0.019	-0.0805	0.1483	-0.2373	0.4932	0.2093	-0.4208	0.2573	0.0954	-0.0014	-0.0102	0.1753	-0.0539	0.2667	-20.5518	25.7819	-33.5763
16	0.6117	0.0924	-0.2746	0.8803	0.2875	0.7985	-0.0731	-0.0321	-0.1009	-0.0537	0.0241	0.0368	0.0875	0.0706	0.0491	0.1947	0.0299	0.011	0.1249	0.0011	0.1437	3.1963	15.8118	-34.2174

Refinement TLS group

ID	Refine-ID	Refine TLS-ID	Selection details
1	X-RAY DIFFRACTION	1	(chain A and resid 33:70)
2	X-RAY DIFFRACTION	2	(chain A and resid 71:134)
3	X-RAY DIFFRACTION	3	(chain A and resid 135:165)
4	X-RAY DIFFRACTION	4	(chain A and resid 166:276)
5	X-RAY DIFFRACTION	5	(chain A and resid 277:315)
6	X-RAY DIFFRACTION	6	(chain A and resid 316:410)
7	X-RAY DIFFRACTION	7	(chain A and resid 411:451)
8	X-RAY DIFFRACTION	8	(chain A and resid 452:577)
9	X-RAY DIFFRACTION	9	(chain B and resid 31:70)
10	X-RAY DIFFRACTION	10	(chain B and resid 71:134)
11	X-RAY DIFFRACTION	11	(chain B and resid 135:165)
12	X-RAY DIFFRACTION	12	(chain B and resid 166:276)
13	X-RAY DIFFRACTION	13	(chain B and resid 277:315)
14	X-RAY DIFFRACTION	14	(chain B and resid 316:410)
15	X-RAY DIFFRACTION	15	(chain B and resid 411:451)
16	X-RAY DIFFRACTION	16	(chain B and resid 452:578)

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