Abstract
GabR from Bacillus subtilis is a transcriptional regulator of the MocR subfamily of GntR regulators. The MocR architecture is characterized by the presence of an N-terminal winged-Helix-Turn-Helix domain and a C-terminal domain folded as the pyridoxal 5′-phosphate (PLP) dependent aspartate aminotransferase (AAT). The two domains are linked by a peptide bridge. GabR activates transcription of genes involved in γ-amino butyrate (GABA) degradation upon binding of PLP and GABA. This work is aimed at contributing to the understanding of the molecular mechanism underlying the GabR transcription activation upon GABA binding. To this purpose, the structure of the entire GabR dimer with GABA external aldimine (holo-GABA) has been reconstructed using available crystallographic data. The structure of the apo (without any ligand) and holo (with PLP) GabR forms have been derived from the holo-GABA. An extensive 1 μs comparative molecular dynamics (MD) has been applied to the three forms. Results showed that the presence of GABA external aldimine stiffens the GabR, stabilizes the AAT domain in the closed form and couples the AAT and HTH domains dynamics. Apo and holo GabR appear more flexible especially at the level of the HTH and linker portions and small AAT subdomain.
Highlights
GabR from Bacillus subtilis is a transcriptional regulator of the MocR subfamily of GntR regulators
This study reports on a 1 μs molecular dynamics (MD) simulation carried out on the three GabR forms, apo, holo and holo-genes involved in γ-amino butyrate (GABA) (PLP-GABA external aldimine)
In this work we have been focusing on the GabR25 a transcriptional regulator belonging to the MocR family, a newly discovered group of regulators structurally related to the fold-type I pyridoxal 5′-phosphate (PLP)-dependent enzymes[1]
Summary
GabR from Bacillus subtilis is a transcriptional regulator of the MocR subfamily of GntR regulators. A GntR subfamily was named MocR after designation of the regulator of rhizopine catabolism genes[3] This subfamily is characterized by a large C-terminal domain (about 350 residues) folded as the type-I pyridoxal 5′-phosphate (PLP)-dependent enzymes[4]. Most of the fold type-I enzymes undergo a transition from an open to a closed conformation upon substrate binding This change, described in detail for the aspartate aminotransferase[7], consists in the closure of the small and large subdomains and it is deemed to be essential for catalysis. The dimeric GabR tertiary structure has been solved in the apo form (with imidazole at the AAT domain active site) and in holo form as an internal aldimine complex with PLP4,28. This conformational change is considered an important component of the mechanism of transcription activation by GABA binding
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