Probing conformational states of glutaryl-CoA dehydrogenase by fragment screening.
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Begley DW, Davies DR, Hartley RC, Hewitt SN, Rychel AL, Myler PJ, Van Voorhis WC, Staker BL, Stewart LJ
Probing conformational states of glutaryl-CoA dehydrogenase by fragment screening.
Acta Crystallogr Sect F Struct Biol Cryst Commun. 2011 Sep 1;67(Pt 9):1060-9. doi: 10.1107/S1744309111014436. Epub 2011 Aug 13.
- PubMed ID
- 21904051 [ View in PubMed]
- Abstract
Glutaric acidemia type 1 is an inherited metabolic disorder which can cause macrocephaly, muscular rigidity, spastic paralysis and other progressive movement disorders in humans. The defects in glutaryl-CoA dehydrogenase (GCDH) associated with this disease are thought to increase holoenzyme instability and reduce cofactor binding. Here, the first structural analysis of a GCDH enzyme in the absence of the cofactor flavin adenine dinucleotide (FAD) is reported. The apo structure of GCDH from Burkholderia pseudomallei reveals a loss of secondary structure and increased disorder in the FAD-binding pocket relative to the ternary complex of the highly homologous human GCDH. After conducting a fragment-based screen, four small molecules were identified which bind to GCDH from B. pseudomallei. Complex structures were determined for these fragments, which cause backbone and side-chain perturbations to key active-site residues. Structural insights from this investigation highlight differences from apo GCDH and the utility of small-molecular fragments as chemical probes for capturing alternative conformational states of preformed protein crystals.