8VXK

Crystal Structure of the Apo Bacillus subtilis GabR C-terminal Effector-binding and Oligomerization Domain

8VXK の概要

• エントリーDOI: 10.2210/pdb8vxk/pdb
• 分子名称: HTH-type transcriptional regulatory protein GabR, PHOSPHATE ION (3 entities in total)
• 機能のキーワード: mocr, gabr, plp, transcription regulator, transcription
• 由来する生物種: Bacillus subtilis
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 88500.21

構造登録者

Kaley, N.E.,Liu, D. (登録日: 2024-02-05, 公開日: 2025-01-08)

主引用文献

Kaley, N.E.,Liveris, Z.J.,Moore, M.,Reidl, C.T.,Wawrzak, Z.,Becker, D.P.,Liu, D.
Bioisosteric replacement of pyridoxal-5'-phosphate to pyridoxal-5'-tetrazole targeting Bacillus subtilis GabR.
Protein Sci., 34:e70014-e70014, 2025

PubMed Abstract: Antimicrobial resistance is a significant cause of mortality globally due to infections, a trend that is expected to continue to rise. As existing treatments fail and new drug discovery slows, the urgency to develop novel antimicrobial therapeutics grows stronger. One promising strategy involves targeting bacterial systems exclusive to pathogens, such as the transcription regulator protein GabR. Expressed in diverse bacteria including Escherichia coli, Bordetella pertussis, and Klebsiella pneumoniae, GabR has no homolog in eukaryotes, making it an ideal therapeutic target. Bacillus subtilis GabR (bsGabR), the most studied variant, regulates its own transcription and activates genes for GABA aminotransferase (GabT) and succinic semialdehyde dehydrogenase (GabD). This intricate regulatory system presents a compelling antimicrobial target with the potential for agonistic intervention to disrupt bacterial gene expression and induce cellular dysfunction, especially in bacterial stress responses. To explore manipulation of this system and the potential of this protein as an antimicrobial target, an in-depth understanding of the unique PLP-dependent transcription regulation is critical. Herein, we report the successful structural modification of the cofactor PLP and demonstrate the biochemical reactivity of the PLP analog pyridoxal-5'-tetrazole (PLT). Through both spectrophotometric and X-ray crystallographic analyses, we explore the interaction between bsGabR and PLT, together with a synthesized GABA derivative (S)-4-amino-5-phenoxypentanoate (4-phenoxymethyl-GABA or 4PMG). Most notably, we present a crystal structure of the condensed, external aldimine complex within bsGabR. While PLT alone is not a drug candidate, it can act as a probe to study the detailed mechanism of GabR-mediated function. PLT employs a tetrazole moiety as a bioisosteric replacement for phosphate in PLP. In addition, the PLP-4PMG adduct observed in the structure may serve as a novel chemical scaffold for subsequent structure-based antimicrobial design.

PubMed: 39720892
DOI: 10.1002/pro.70014

実験手法

X-RAY DIFFRACTION (1.85 Å)