3D6B: 2.2 A Crystal Structure Of Glutaryl-coa Dehydrogenase From Burkholderia Pseudomallei

Citation:
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.
PDB ID: 3D6BDownload
MMDB ID: 64805
PDB Deposition Date: 2008/5/19
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.21  Å
Source Organism:
Similar Structures:
Biological Unit for 3D6B: tetrameric; determined by software (PISA)
Molecular Components in 3D6B
Label Count Molecule
Proteins (4 molecules)
4
Glutaryl-coa Dehydrogenase
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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