TITLE

Crystal structure of a bacterial cocaine esterase

AUTHOR(S)
Larsen, Nicholas A.; Turner, James M.; Stevens, James; Rosser, Susan J.; Basran, Amrik; Lerner, Richard A.; Bruce, Neil C.; Wilson, Ian A.
PUB. DATE
January 2002
SOURCE
Nature Structural Biology;Jan2002, Vol. 9 Issue 1, p17
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Here we report the first structure of a cocaine-degrading enzyme. The bacterial esterase, cocE, hydrolyzes pharmacologically active (-)-cocaine to a nonpsychoactive metabolite with a rate faster than any other reported cocaine esterase (kcat = 7.8 s-1 and KM = 640 nM). Because of the high catalytic proficiency of cocE, it is an attractive candidate for novel protein-based therapies for cocaine overdose. The crystal structure of cocE, solved by multiple anomalous dispersion (MAD) methods, reveals that cocE is a serine esterase composed of three domains: (i) a canonical α/β hydrolase fold (ii) an α-helical domain that caps the active site and (iii) a jelly-roll-like β-domain that interacts extensively with the other two domains. The active site was identified within the interface of all three domains by analysis of the crystal structures of transition state analog adduct and product complexes, which were refined at 1.58 Å and 1.63 Å resolution, respectively. These structural studies suggest that substrate recognition arises partly from interactions between the benzoyl moiety of cocaine and a highly evolved specificity pocket.
ACCESSION #
8782001

 

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