5FPO

Structure of Bacterial DNA Ligase with small-molecule ligand 1H- indazol-7-amine (AT4213) in an alternate binding site.

5FPO の概要

• エントリーDOI: 10.2210/pdb5fpo/pdb
• 関連するPDBエントリー: 5FP5 5FP6 5FPD 5FPE 5FPM 5FPN 5FPR 5FPS 5FPT 5FPY
• 分子名称: DNA LIGASE, 1H-indazol-7-amine (3 entities in total)
• 機能のキーワード: ligase, antibiotic design, protein-ligand complex, fragment screening, alternate binding site, at4213.
• 由来する生物種: STAPHYLOCOCCUS AUREUS
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37124.24

構造登録者

Jhoti, H.,Ludlow, R.F.,Pathuri, P.,Saini, H.K.,Tickle, I.J.,Tisi, D.,Verdonk, M.,Williams, P.A. (登録日: 2015-12-02, 公開日: 2015-12-23, 最終更新日: 2024-01-10)

主引用文献

Ludlow, R.F.,Verdonk, M.L.,Saini, H.K.,Tickle, I.J.,Jhoti, H.
Detection of Secondary Binding Sites in Proteins Using Fragment Screening.
Proc.Natl.Acad.Sci.USA, 112:15910-, 2015

PubMed Abstract: Proteins need to be tightly regulated as they control biological processes in most normal cellular functions. The precise mechanisms of regulation are rarely completely understood but can involve binding of endogenous ligands and/or partner proteins at specific locations on a protein that can modulate function. Often, these additional secondary binding sites appear separate to the primary binding site, which, for example for an enzyme, may bind a substrate. In previous work, we have uncovered several examples in which secondary binding sites were discovered on proteins using fragment screening approaches. In each case, we were able to establish that the newly identified secondary binding site was biologically relevant as it was able to modulate function by the binding of a small molecule. In this study, we investigate how often secondary binding sites are located on proteins by analyzing 24 protein targets for which we have performed a fragment screen using X-ray crystallography. Our analysis shows that, surprisingly, the majority of proteins contain secondary binding sites based on their ability to bind fragments. Furthermore, sequence analysis of these previously unknown sites indicate high conservation, which suggests that they may have a biological function, perhaps via an allosteric mechanism. Comparing the physicochemical properties of the secondary sites with known primary ligand binding sites also shows broad similarities indicating that many of the secondary sites may be druggable in nature with small molecules that could provide new opportunities to modulate potential therapeutic targets.

PubMed: 26655740
DOI: 10.1073/PNAS.1518946112

実験手法

X-RAY DIFFRACTION (1.83 Å)