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Title: Probing conformational states of glutaryl-CoA dehydrogenase by fragment screening

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.
Authors:
; ; ; ; ; ; ; ;  [1]
  1. (Emerald)
Publication Date:
OSTI Identifier:
1027143
Resource Type:
Journal Article
Resource Relation:
Journal Name: Acta Crystallogr. F; Journal Volume: 67; Journal Issue: (9) ; 09, 2011
Research Org:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Org:
NIHNIAIDOTHER U.S. GOVERNMENT
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ADENINES; DEFECTS; DISEASES; ENZYMES; INSTABILITY; ISOALLOXAZINES; OXIDOREDUCTASES; PROBES; PROTEINS; RESIDUES