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(S)-4-Amino-5-phenoxypentanoate designed as a potential selective agonist of the bacterial transcription factor GabR.
Protein Science ( IF 8 ) Pub Date : 2020-06-18 , DOI: 10.1002/pro.3905
Daniel S Catlin 1 , Cory T Reidl 1 , Thomas R Trzupek 2 , Richard B Silverman 2, 3 , Brian L Cannon 4 , Daniel P Becker 1 , Dali Liu 1
Affiliation  

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.

中文翻译:

(S)-4-Amino-5-phenoxypentanoate 被设计为细菌转录因子 GabR 的潜在选择性激动剂。

在进化背景下解决分子识别问题需要寻求新的分子靶点,以开发具有新作用机制的激动剂或拮抗剂。通过靶向调节细菌代谢中关键酶表达的转录因子来破坏转录调控可能为控制细菌代谢途径提供一种有前景的方法。为此,我们通过设计和合成一系列γ-氨基丁酸(GABA)衍生物,包括(S)-4-氨基-5-苯氧基戊酸酯(4-苯氧基甲基-GABA),选择性地靶向细菌转录调节因子,这是基于从先前解决的枯草芽孢杆菌GabR 晶体结构中获得的对接见解. 选择这个目标是因为 GabR 通过调节 gabT/D 操纵子的转录来严格控制 GABA 代谢。这些 GabR 转录调节剂对细菌转录因子 GabR 具有选择性,并且由于不同的空间限制而无法与 GabR 的结构同源物结合。我们在 GabR 的效应子结合位点获得了 4-苯氧基甲基-GABA 作为外部醛亚胺与 PLP 结合的晶体结构,这表明该化合物能够以与天然效应子配体相同的方式结合和反应。抑制试验表明 4-苯氧基甲基-GABA 对细菌 GabR 的选择性比几种选定的真核酶高。
更新日期:2020-07-24
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