PDB-3ppm: Crystal Structure of a Noncovalently Bound alpha-Ketoheterocycle ...

ID or keywords:

Entry

Database: PDB / ID: 3ppm

Title

Crystal Structure of a Noncovalently 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 /

oxazole /

oxadiazole / endocannabinoid degradation /

membrane protein / 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 /

acylglycerol 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: 1.78 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 24, 2010	Deposition site: RCSB / Processing site: RCSB
Revision 1.0	Nov 9, 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_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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

Structure viewer	Molecule: MolmilJmol/JSmol

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Download

PDBx/mmCIF format	3ppm.cif.gz	450.6 KB	Display	PDBx/mmCIF format
PDB format	pdb3ppm.ent.gz	369.7 KB	Display	PDB format
PDBx/mmJSON format	3ppm.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/pp/3ppm ftp://data.pdbj.org/pub/pdb/validation_reports/pp/3ppm	HTTPS FTP

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Related structure data

Related structure data	3pr0C 2wj1S 2wj2 3k7f 3k83 3k84 S: Starting model for refinement C: citing same article (ref.)
Similar structure data	3lj7-d 3k83-d 3pr0-d 3lj6-d 4do3-d 1mt5-1 3k84-d 3qj9-d 3qkv-d 2wap-d 1mt5-5 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

128 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)	103.692, 103.692, 254.705
Angle α, β, γ (deg.)	90.00, 90.00, 120.00
Int Tables number	154
Space group name H-M	P3₂21

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Protein , 1 types, 2 molecules AB

#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, fatty acid amide hydrolase

#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,

fatty acid amide hydrolase

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Non-polymers , 6 types, 1066 molecules

#2: Chemical	ChemComp-JG1 / 7-phenyl-1-[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]heptan-1-one Mass: 335.400 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C₂₀H₂₁N₃O₂
#3: Chemical	ChemComp-CL / CHLORIDE ION / Chloride Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#4: Chemical	ChemComp-F / FLUORIDE ION / Fluoride Mass: 18.998 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: F
#5: Chemical	ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol Mass: 106.120 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C₄H₁₀O₃
#6: Chemical	ChemComp-1DO / 1-DODECANOL / Dodecanol Mass: 186.334 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C₁₂H₂₆O
#7: Water	ChemComp-HOH / water / Water Mass: 18.015 Da / Num. of mol.: 1054 / 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: 3.13 Å³/Da / Density % sol: 60.72 %
Crystal grow	Temperature: 287 K / Method: vapor diffusion / pH: 5.5 Details: 30% PEG400, 100 mM Mes pH 5.5, 100 mM KCl, 200 mM NaCl, 100 mM NaF, and 8% polypropylene glycol-P400, VAPOR DIFFUSION, 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 21, 2008
Radiation	Monochromator: Side scattering bent cube-root I-beam single crystal; asymmetric cut 4.965 degs Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelength	Wavelength: 0.97945 Å / Relative weight: 1
Reflection	Resolution: 1.78→33.94 Å / Num. all: 152465 / Num. obs: 151855 / % possible obs: 99.6 % / Observed criterion σ(I): -3 / Redundancy: 3.9 % / B_iso Wilson estimate: 22.4 Å² / R_sym value: 0.058 / Net I/σ(I): 20
Reflection shell	Resolution: 1.78→1.81 Å / Redundancy: 2.8 % / Mean I/σ(I) obs: 2 / Num. unique all: 7439 / R_sym value: 0.454 / % possible all: 99

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Processing

Software

Name	Version	Classification
HKL-2000		data collection
PHASER		phasing
PHENIX	(phenix.refine: 1.6.4_486)	refinement
HKL-2000		data reduction
HKL-2000		data scaling

Refinement

Method to determine structure:

MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2WJ1

2wj1

Resolution: 1.78→33.94 Å / SU ML: 0.2
Isotropic thermal model: isotropic + 16 groups tls (8 each monomer)
Cross valid method: THROUGHOUT / σ(F): 1.34 / Stereochemistry target values: ML

	R_factor	Num. reflection	% reflection	Selection details
R_free	0.1764	7621	5.02 %	Copied set from model
R_work	0.1512	-	-	-
obs	0.1525	151735	99.56 %	-

Solvent computation

Shrinkage radii: 0.83 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / B_sol: 47.846 Å² / k_sol: 0.338 e/Å³

Displacement parameters

B_iso mean: 25.5 Å²

	B_aniso -1	B_aniso -2	B_aniso -3
1-	1.6249 Å²	-0 Å²	-0 Å²
2-	-	1.6249 Å²	-0 Å²
3-	-	-	-3.2497 Å²

Refinement step

Cycle: LAST / Resolution: 1.78→33.94 Å

	Protein	Nucleic acid	Ligand	Solvent	Total
Num. atoms	8421	0	96	1054	9571

Refine LS restraints

Refine-ID	Type	Dev ideal	Number
X-RAY DIFFRACTION	f_bond_d	0.007	8866
X-RAY DIFFRACTION	f_angle_d	1.081	12047
X-RAY DIFFRACTION	f_dihedral_angle_d	12.542	3400
X-RAY DIFFRACTION	f_chiral_restr	0.073	1343
X-RAY DIFFRACTION	f_plane_restr	0.005	1559

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 (%)
1.78-1.8002	0.2932	244	0.2756	4677	X-RAY DIFFRACTION	99
1.8002-1.8214	0.2896	249	0.2522	4805	X-RAY DIFFRACTION	100
1.8214-1.8436	0.2595	261	0.2227	4737	X-RAY DIFFRACTION	100
1.8436-1.8669	0.2363	267	0.2112	4761	X-RAY DIFFRACTION	100
1.8669-1.8915	0.2344	252	0.1898	4764	X-RAY DIFFRACTION	100
1.8915-1.9174	0.1981	242	0.1722	4780	X-RAY DIFFRACTION	100
1.9174-1.9448	0.1967	226	0.1632	4785	X-RAY DIFFRACTION	100
1.9448-1.9738	0.1857	244	0.1619	4799	X-RAY DIFFRACTION	100
1.9738-2.0047	0.2067	253	0.1536	4778	X-RAY DIFFRACTION	100
2.0047-2.0375	0.1805	251	0.1502	4815	X-RAY DIFFRACTION	100
2.0375-2.0727	0.1813	251	0.1449	4759	X-RAY DIFFRACTION	100
2.0727-2.1104	0.1836	247	0.143	4808	X-RAY DIFFRACTION	100
2.1104-2.1509	0.1636	252	0.1411	4769	X-RAY DIFFRACTION	100
2.1509-2.1948	0.1754	255	0.1363	4800	X-RAY DIFFRACTION	100
2.1948-2.2426	0.1451	276	0.1395	4755	X-RAY DIFFRACTION	100
2.2426-2.2947	0.185	236	0.1423	4836	X-RAY DIFFRACTION	100
2.2947-2.3521	0.1801	265	0.1427	4786	X-RAY DIFFRACTION	100
2.3521-2.4157	0.1901	269	0.1411	4784	X-RAY DIFFRACTION	100
2.4157-2.4867	0.1624	269	0.135	4752	X-RAY DIFFRACTION	100
2.4867-2.567	0.1712	243	0.1424	4851	X-RAY DIFFRACTION	100
2.567-2.6587	0.1739	269	0.1468	4798	X-RAY DIFFRACTION	100
2.6587-2.7651	0.1973	258	0.1513	4807	X-RAY DIFFRACTION	100
2.7651-2.8909	0.1724	248	0.1516	4861	X-RAY DIFFRACTION	100
2.8909-3.0432	0.1756	239	0.1566	4865	X-RAY DIFFRACTION	100
3.0432-3.2337	0.1702	273	0.1501	4814	X-RAY DIFFRACTION	100
3.2337-3.4831	0.1495	258	0.1469	4838	X-RAY DIFFRACTION	100
3.4831-3.8332	0.1562	247	0.1374	4872	X-RAY DIFFRACTION	99
3.8332-4.3869	0.1735	254	0.137	4859	X-RAY DIFFRACTION	99
4.3869-5.5232	0.1483	267	0.1335	4859	X-RAY DIFFRACTION	98
5.5232-33.9473	0.184	256	0.1727	4940	X-RAY DIFFRACTION	95

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	0.8273	0.0721	0.385	0.9411	0.3527	0.435	-0.048	0.4349	-0.0302	-0.3739	-0.0432	0.2082	-0.0576	-0.0704	0.0645	0.2877	-0.027	-0.0949	0.3525	0.0248	0.2005	23.2008	-33.8612	-14.42
2	1.0338	-0.3517	0.2695	1.6312	-0.4897	0.7429	-0.0961	0.1938	0.0945	-0.2367	0.0267	0.2746	-0.2312	-0.1918	0.0357	0.1882	0.0243	-0.064	0.1958	0.0467	0.1733	24.918	-19.2981	-5.1822
3	0.1482	-0.2547	-0.2063	1.9378	0.6086	0.5699	0.0256	0.1208	-0.0464	-0.0357	-0.1238	0.2632	0.0359	-0.2947	0.0993	0.1576	-0.0128	-0.0206	0.2445	-0.015	0.1904	23.2645	-37.2489	0.4736
4	0.2122	-0.0671	0.1099	0.4714	0.1597	0.4161	-0.0095	0.0993	-0.0147	-0.0759	0.0062	0.0286	-0.018	-0.0084	-0.001	0.1426	-0.0129	-0.0029	0.1758	0.0075	0.1267	34.101	-33.5383	2.597
5	0.2034	0.133	0.2039	0.072	0.1323	0.7582	-0.0198	-0.0013	0.022	0.0052	-0.0137	0.0406	-0.1087	-0.0525	0.0266	0.1623	0.0099	0.0057	0.1661	0.0257	0.161	29.1939	-24.349	14.2577
6	0.2445	0.0898	-0.0552	0.7656	0.1208	0.6196	-0.0035	0.0271	-0.0333	-0.0131	0.0134	-0.0937	0.0043	0.1321	-0.0006	0.0837	-0.0168	0.0093	0.1446	0.0095	0.1147	48.5264	-34.8416	10.9307
7	1.6524	-0.4314	-1.1985	0.3893	0.2544	1.5111	-0.0614	-0.0972	-0.1753	-0.0119	-0.0979	-0.1231	0.2776	0.2012	0.1333	0.1614	0.0462	0.0285	0.1589	0.0239	0.1811	48.4145	-54.7916	16.417
8	0.4207	-0.0053	-0.0247	0.4514	-0.1555	0.7156	0.0019	0.0283	0.0242	-0.0453	0.0146	-0.0674	-0.0437	0.1257	-0.0076	0.1145	-0.0188	0.0179	0.1615	0.0038	0.1263	50.2792	-30.0279	8.8301
9	0.1796	0.1339	0.2375	0.3026	-0.1496	0.7784	0.0605	-0.1151	-0.0475	0.0413	-0.2304	-0.0347	-0.0622	-0.1118	0.1323	0.1606	-0.0044	-0.027	0.2599	-0.0026	0.1723	40.843	-38.4508	64.3126
10	0.7146	0.4592	0.0731	0.8862	0.1986	0.7297	-0.0385	-0.1336	0.0831	0.163	0.0299	-0.08	-0.2022	0.0557	0.0144	0.1667	-0.0175	-0.0063	0.1808	-0.0306	0.16	33.8897	-24.4606	57.7939
11	0.0147	-0.0517	-0.0445	1.4403	-0.1975	0.2295	0.039	-0.0235	0.0121	0.0379	-0.0895	-0.2253	-0.0183	0.1358	0.0458	0.1006	-0.0031	-0.0069	0.1634	0.0087	0.1498	41.8873	-39.5421	48.7588
12	0.1143	-0.0477	0.0527	0.2338	-0.1012	0.347	-0.0071	-0.0347	-0.0417	-0.0008	-0.0005	-0.0135	0.0166	-0.0059	0.0047	0.1094	-0.0033	0.0059	0.1528	0.0008	0.1399	30.3095	-39.31	47.062
13	0.1585	-0.0333	0.2053	0.1726	-0.1807	0.6648	0.0017	-0.0046	0.0514	-0.0022	0.0108	0.038	-0.0582	0.0101	0.005	0.1433	-0.0078	0.0064	0.1601	0.0022	0.1491	30.8664	-26.5377	37.8408
14	0.3619	0.0669	-0.0494	0.4113	-0.0182	0.4272	-0.0176	0.0346	-0.0158	-0.0035	0.0263	0.0743	0.0325	-0.1153	-0.0087	0.0782	-0.0135	0.0118	0.1339	-0.0035	0.1078	17.2915	-44.3381	38.1685
15	1.6743	0.3447	-0.8718	0.1403	-0.3352	0.7583	-0.1751	0.2517	-0.3421	-0.0425	-0.0203	-0.0066	0.2618	-0.1922	0.1967	0.1806	-0.0574	0.0627	0.1154	-0.0694	0.1974	24.2353	-61.0169	28.7098
16	0.5223	0.096	-0.1111	0.3483	-0.0985	0.3406	0.0064	0.0109	0.007	0.0045	0.015	0.0434	-0.0099	-0.0859	-0.0176	0.0402	-0.0032	0.0087	0.1105	0.0017	0.0784	13.7315	-40.9369	41.0943

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 452:578)
9	X-RAY DIFFRACTION	9	(chain B and resid 33:70)
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 452:577)

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