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PDBsum entry 5c8v
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References listed in PDB file
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Key reference
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Title
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Conformational disorganization within the active site of a recently evolved organophosphate hydrolase limits its catalytic efficiency.
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Authors
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P.D.Mabbitt,
G.J.Correy,
T.Meirelles,
N.J.Fraser,
M.L.Coote,
C.J.Jackson.
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Ref.
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Biochemistry, 2016,
55,
1408-1417.
[DOI no: ]
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PubMed id
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Abstract
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The evolution of new enzymatic activity is rarely observed outside of the
laboratory. In the agricultural pest Lucilia cuprina, a naturally occurring
mutation (Gly137Asp) in α-esterase 7 (LcαE7) results in acquisition of
organophosphate hydrolase activity and confers resistance to organophosphate
insecticides. Here, we present an X-ray crystal structure of LcαE7:Gly137Asp
that, along with kinetic data, suggests that Asp137 acts as a general base in
the new catalytic mechanism. Unexpectedly, the conformation of Asp137 observed
in the crystal structure obstructs the active site and is not catalytically
productive. Molecular dynamics simulations reveal that alternative,
catalytically competent conformers of Asp137 are sampled on the nanosecond time
scale, although these states are less populated. Thus, although the mutation
introduces the new reactive group responsible for organophosphate
detoxification, the catalytic efficiency appears to be limited by conformational
disorganization: the frequent sampling of low-energy nonproductive states. This
result is consistent with a model of molecular evolution in which initial
function-changing mutations can result in enzymes that display only a fraction
of their catalytic potential due to conformational disorganization.
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