Download MendeleyProbing conformational states of glutaryl-CoA dehydrogenase by fragment screening.
Begley, D.W., Davies, D.R., Hartley, R.C., Hewitt, S.N., Rychel, A.L., Myler, P.J., Van Voorhis, W.C., Staker, B.L., Stewart, L.J.(2011) Acta Crystallogr Sect F Struct Biol Cryst Commun 67: 1060-1069
- PubMed: 21904051
- DOI: https://doi.org/10.1107/S1744309111014436
- Primary Citation of Related Structures:
3D6B, 3EOM, 3EON, 3GNC, 3GQT - 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.
Organizational Affiliation:
Seattle Structural Genomics Center for Infectious Disease (http://www.ssgcid.org), USA. dbegley@embios.com
