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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
OpenAccess logo Acta Crystallogr Sect F Struct Biol Cryst Commun 67 1060-9 (2011)
Related entries: 3d6b, 3eon, 3gnc, 3gqt

Cited: 3 times
EuropePMC logo PMID: 21904051

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.

Reviews - 3eom mentioned but not cited (1)

  1. The Seattle Structural Genomics Center for Infectious Disease (SSGCID). Myler PJ, Stacy R, Stewart L, Staker BL, Van Voorhis WC, Varani G, Buchko GW. Infect Disord Drug Targets 9 493-506 (2009)

Articles - 3eom mentioned but not cited (2)

  1. 3-Sulfinopropionyl-coenzyme A (3SP-CoA) desulfinase from Advenella mimigardefordensis DPN7(T): crystal structure and function of a desulfinase with an acyl-CoA dehydrogenase fold. Schürmann M, Meijers R, Schneider TR, Steinbüchel A, Cianci M. Acta Crystallogr. D Biol. Crystallogr. 71 1360-1372 (2015)
  2. Probing conformational states of glutaryl-CoA dehydrogenase by fragment screening. Begley DW, Davies DR, Hartley RC, Hewitt SN, Rychel AL, Myler PJ, Van Voorhis WC, Staker BL, Stewart LJ. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 67 1060-1069 (2011)




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