3ida

Thermostable Cocaine Esterase with mutations L169K and G173Q, bound to DTT adduct

spinqualitylabelsall models 3ida, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3ida is a 1 chain structure with sequence from Corynebacterium sp. atcc 49955. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CL, DBC, GOL Related: 3i2k, 3i2j, 3i2i, 3i2g Gene: cocE (Corynebacterium sp. ATCC 49955) Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [COCE_RHOSM] Hydrolyzes cocaine to benzoate and ecgonine methyl ester, endowing the bacteria with the ability to utilize cocaine as a sole source of carbon and energy for growth, as this bacterium lives in the rhizosphere of coca plants. Also efficiently hydrolyzes cocaethylene, a more potent cocaine metabolite that has been observed in patients who concurrently abuse cocaine and alcohol. Is able to prevent cocaine-induced convulsions and lethality in rat. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Rhodococcal cocaine esterase (CocE) is an attractive potential treatment for both cocaine overdose and cocaine addiction. CocE directly degrades cocaine into inactive products, whereas traditional small-molecule approaches require blockade of the inhibitory action of cocaine on a diverse array of monoamine transporters and ion channels. The usefulness of wild-type (wt) cocaine esterase is hampered by its inactivation at 37 degrees C. Herein, we characterize the most thermostable form of this enzyme to date, CocE-L169K/G173Q. In vitro kinetic analyses reveal that CocE-L169K/G173Q displays a half-life of 2.9 days at 37 degrees C, which represents a 340-fold improvement over wt and is 15-fold greater than previously reported mutants. Crystallographic analyses of CocE-L169K/G173Q, determined at 1.6-A resolution, suggest that stabilization involves enhanced domain-domain interactions involving van der Waals interactions and hydrogen bonding. In vivo rodent studies reveal that intravenous pretreatment with CocE-L169K/G173Q in mice provides protection from cocaine-induced lethality for longer time periods before cocaine administration than wt CocE. Furthermore, intravenous administration (pretreatment) of CocE-L169K/G173Q prevents self-administration of cocaine in a time-dependent manner. Termination of the in vivo effects of CoCE seems to be dependent on, but not proportional to, its clearance from plasma as its half-life is approximately 2.3 h and similar to that of wt CocE (2.2 h). Taken together these data suggest that CocE-L169K/G173Q possesses many of the properties of a biological therapeutic for treating cocaine abuse but requires additional development to improve its serum half-life. A thermally stable form of bacterial cocaine esterase: a potential therapeutic agent for treatment of cocaine abuse.,Brim RL, Nance MR, Youngstrom DW, Narasimhan D, Zhan CG, Tesmer JJ, Sunahara RK, Woods JH Mol Pharmacol. 2010 Apr;77(4):593-600. Epub 2010 Jan 19. PMID:20086035 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cocaine esterase

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