3D6B

2.2 A crystal structure of glutaryl-CoA dehydrogenase from Burkholderia pseudomallei

Summary for 3D6B

• Entry DOI: 10.2210/pdb3d6b/pdb
• Descriptor: Glutaryl-CoA dehydrogenase, methyl thiophene-2-carboxylate (3 entities in total)
• Functional Keywords: burkholderia, pseudomallei, glutaryl-coa, dehydrogenase, seattle structural genomics center for infectious disease, ssgcid, fad, flavoprotein, oxidoreductase
• Biological source: Burkholderia pseudomallei
• Total number of polymer chains: 4
• Total formula weight: 172819.18

Authors

Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2008-05-19, release date: 2008-06-03, Last modification date: 2024-02-21)

Primary citation

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.
Probing conformational states of glutaryl-CoA dehydrogenase by fragment screening.
Acta Crystallogr.,Sect.F, 67:1060-1069, 2011

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.

PubMed: 21904051
DOI: 10.1107/S1744309111014436

Experimental method

X-RAY DIFFRACTION (2.21 Å)