Active-Site Dynamics of ASADH—A Bacterial Biosynthetic Enzyme

Active-Site Dynamics of ASADH—A Bacterial Biosynthetic Enzyme

Active-Site Dynamics of ASADH—A Bacterial Biosynthetic Enzyme

ABSTRACT: Aspartate b-semialdehyde dehydrogenase ASADH is an important  .
enzyme in the synthesis of essential amino acids and therefore an attractive target for
antibacterial, fungicidal, or herbicidal agents. The structure of the enzyme has recently
been determined by X-ray crystallography Hadfield et al  . ., submitted for publication
both in the presence and absence of its cofactor, NADP, and likely catalytic residues have
been identified. Comparison of the structures reveals both global and local conformational
changes: In the complex structure, the NADP binding domain moves closer to the
substrate binding domain, and side chains involved in substrate binding are reoriented.
In addition, a loop region which is not observed in the structure of the apo enzyme
becomes ordered and is found close to the active site. To examine the structure of this
loop in the native enzyme and to study the dynamics and interactions at the active site,
we performed molecular dynamics simulations of ASADH with a stochastic boundary
technique. Multiple simulated annealing refinements against the crystallographic data
were also performed to examine structural variability in the native and complexed
enzyme. The results shed light on the active-site structure and dynamics of this important
enzyme

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