High-resolution structures reveal details of domain closure and "half-of-sites-reactivity" in Escherichia coli aspartate beta-semialdehyde dehydrogenase.
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.
Nichols
C E
CE
Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
Dhaliwal
B
B
Lockyer
M
M
Hawkins
A R
AR
Stammers
D K
DK
D001223:Aspartate-Semialdehyde Dehydrogenase / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019992:Databases as Topic; D019281:Dimerization; D004926:Escherichia coli / Q000201:enzymology*; D008956:Models, Chemical; D008958:Models, Molecular; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
D001223:Aspartate-Semialdehyde Dehydrogenase