6UXZ

(S)-4-Amino-5-phenoxypentanoate as a Selective Agonist of the Transcription Factor GabR

6UXZ の概要

• エントリーDOI: 10.2210/pdb6uxz/pdb
• 分子名称: HTH-type transcriptional regulatory protein GabR, SULFATE ION, (4S)-4-[(E)-({3-hydroxy-2-methyl-5-[(phosphonooxy)methyl]pyridin-4-yl}methylidene)amino]-5-phenoxypentanoic acid (3 entities in total)
• 機能のキーワード: gabr transcription factor, selective agonist gaba. metabolism, transcription
• 由来する生物種: Bacillus subtilis (strain 168)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 85269.11

構造登録者

Catlin, D.S.,Liu, D. (登録日: 2019-11-09, 公開日: 2020-10-07, 最終更新日: 2024-04-03)

主引用文献

Catlin, D.S.,Reidl, C.T.,Trzupek, T.R.,Silverman, R.B.,Cannon, B.L.,Becker, D.P.,Liu, D.
(S)-4-Amino-5-phenoxypentanoate designed as a potential selective agonist of the bacterial transcription factor GabR.
Protein Sci., 29:1816-1828, 2020

PubMed Abstract: Addressing molecular recognition in the context of evolution requires pursuing new molecular targets to enable the development of agonists or antagonists with new mechanisms of action. Disruption of transcriptional regulation through targeting transcription factors that regulate the expression of key enzymes in bacterial metabolism may provide a promising method for controlling the bacterial metabolic pathways. To this end, we have selectively targeted a bacterial transcription regulator through the design and synthesis of a series of γ-aminobutyric acid (GABA) derivatives, including (S)-4-amino-5-phenoxypentanoate (4-phenoxymethyl-GABA), which are based on docking insights gained from a previously-solved crystal structure of GabR from Bacillus subtilis. This target was selected because GabR strictly controls GABA metabolism by regulating the transcription of the gabT/D operon. These GabR transcription modulators are selective for the bacterial transcription factor GabR and are unable to bind to structural homologs of GabR due to distinct steric constraints. We have obtained a crystal structure of 4-phenoxymethyl-GABA bound as an external aldimine with PLP in the effector binding site of GabR, which suggests that this compound is capable of binding and reacting in the same manner as the native effector ligand. Inhibition assays demonstrate high selectivity of 4-phenoxymethyl-GABA for bacterial GabR versus several selected eukaryotic enzymes. Single-molecule fluorescence resonance energy transfer (smFRET) experiments reveal a ligand-induced DNA distortion that is very similar to that of the native effector GABA, suggesting that the compound functions as a potential selective agonist of GabR.

PubMed: 32557944
DOI: 10.1002/pro.3905

実験手法

X-RAY DIFFRACTION (2.8 Å)