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Enzyme Specificity Under Dynamic Control: A Normal Mode Analysis of Alpha-Lytic Protease

Enzyme Specificity Under Dynamic Control: A Normal Mode Analysis of Alpha-Lytic Protease

D W Miller, D A Agard

J Mol Biol. 1999 Feb 12;286(1):267-78.

PMID: 9931265

Abstract:

We have used alpha-lytic protease as a model system for exploring the relationship between the internal dynamics of an enzyme and its substrate specificity. The wild-type enzyme is highly specific for small substrates in its primary specificity pocket, while the M190A mutant has a much broader specificity, efficiently catalyzing cleavage of both large and small substrates. Normal modes have been calculated for both the wild-type and the mutant enzyme to determine how internal vibrations contribute to these contrasting specificity profiles. We find that for the atoms lining the walls of the specificity pocket, the wild-type normal modes have a more symmetric character, with the walls vibrating in phase, and the size of the pocket remaining relatively fixed. This is in agreement with X-ray crystallographic data on conformational substates trapped at 120 K. In contrast, we find that in the mutant, the binding pocket normal modes have a more antisymmetric character, with the walls vibrating out of phase, and the pocket able to expand and contract. These results suggest that the internal vibrations of a molecule may play an important role in determining substrate binding and specificity. A small change in protein structure can have a significant effect on the pattern of molecular vibrations, and thus on enzymatic properties, even if the overall amplitudes of the vibrations, as measured by NMR relaxation or crystallographic B-factors, remain largely unchanged.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42410057	Alpha-Lytic Protease M190A Mutant			Price

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