School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
Department of Oncology and Pneumonology, Internal Medicine, University Hospital Tübingen, Otfried-Müller-Straße 10, DE 72076 Tübingen, Germany.
J Chem Inf Model. 2021 Mar 22;61(3):1346-1353. doi: 10.1021/acs.jcim.0c01233. Epub 2021 Mar 8.
Quorum sensing is being investigated as an alternative therapeutic strategy in antibacterial drug discovery programs aimed at combatting bacterial resistance. LsrK is an autoinducer-2 kinase (belongs to the sugar kinase family), playing a key role in the phosphorylation of the autoinducer-2 (AI-2) signaling molecules involved in quorum sensing. Inhibiting LsrK could result in reduced pathogenicity by interfering with quorum sensing signaling. Previously, we have generated homology models to employ in structure-based virtual screening and successfully identified the first class of LsrK inhibitors. While conducting these studies, the crystal structure of LsrK was released, providing us with an opportunity to evaluate the reliability and quality of our models. A comparative structural analysis of the crystal structure and homology models revealed consistencies among them in the overall structural fold and binding site. Furthermore, the binding characteristics and conformational changes of LsrK have been investigated using molecular dynamics to inspect whether LsrK undergoes similar conformational changes as that of sugar kinases. These studies revealed the flexibility of the LsrK C-terminal domain (Domain II) attributing to the conformational changes in LsrK resulting in open and closed states during the phosphorylation. Further, simulations provided us with insights into the flexibility of a loop in Domain I that can influence the ligand accessibility to the LsrK binding site.
群体感应被视为一种替代的治疗策略，用于抗菌药物发现计划，旨在对抗细菌耐药性。LsrK 是一种自动诱导物-2 激酶（属于糖激酶家族），在磷酸化参与群体感应的自动诱导物-2（AI-2）信号分子中起着关键作用。抑制 LsrK 可以通过干扰群体感应信号来降低致病性。以前，我们已经生成了同源模型，用于基于结构的虚拟筛选，并成功地鉴定了第一类 LsrK 抑制剂。在进行这些研究的过程中，释放了 LsrK 的晶体结构，这为我们提供了评估模型可靠性和质量的机会。晶体结构和同源模型的比较结构分析表明，它们在整体结构折叠和结合位点方面具有一致性。此外，还使用分子动力学研究了 LsrK 的结合特性和构象变化，以检查 LsrK 是否经历了与糖激酶相似的构象变化。这些研究揭示了 LsrK C 末端结构域（结构域 II）的灵活性，归因于磷酸化过程中 LsrK 的构象变化导致的开放和关闭状态。此外，模拟为我们提供了对结构域 I 中一个环的灵活性的深入了解，该环可以影响配体对 LsrK 结合位点的可及性。
