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Two high-resolution structures have been determined for Eschericia coli aspartate beta-semialdehyde dehydrogenase (ecASADH), an enzyme of the aspartate biosynthetic pathway, which is a potential target for novel antimicrobial drugs. Both ASADH structures were of the open form and were refined to 1.95 A and 1.6 A resolution, allowing a more detailed comparison with the closed form of the enzyme than previously possible. A more complex scheme for domain closure is apparent with the subunit being split into two further sub-domains with relative motions about three hinge axes. Analysis of hinge data and torsion-angle difference plots is combined to allow the proposal of a detailed structural mechanism for ecASADH domain closure. Additionally, asymmetric distortions of individual subunits are identified, which form the basis for the previously reported "half-of-the-sites reactivity" (HOSR). A putative explanation of this arrangement is also presented, suggesting the HOSR system may provide a means for ecASADH to offset the energy required to remobilise flexible loops at the end of the reaction cycle, and hence avoid falling into an energy minimum.

Original publication

DOI

10.1016/j.jmb.2004.05.073

Type

Journal article

Journal

J Mol Biol

Publication Date

13/08/2004

Volume

341

Pages

797 - 806

Keywords

Aspartate-Semialdehyde Dehydrogenase, Binding Sites, Crystallography, X-Ray, Databases as Topic, Dimerization, Escherichia coli, Models, Chemical, Models, Molecular, Protein Conformation, Protein Structure, Secondary, Protein Structure, Tertiary