Sindhu Thangaraj, Rajamanikandan Sundarraj, Jeyakanthan Jeyaraman, Pal Debnath
Department of Computational and Data Sciences, Indian Institute of Science, Bangalore, Karnataka, India.
Research and Development Wing, Sree Balaji Medical College and Hospital (BIHER), Chennai, Tamil Nadu, India.
J Mol Graph Model. 2023 Jan;118:108347. doi: 10.1016/j.jmgm.2022.108347. Epub 2022 Sep 28.
Cytochrome b (QcrB) is considered an essential subunit in the electron transport chain that coordinates the action of the entire cytochrome bc1 oxidase. It has been identified as an attractive drug target for a new promising clinical candidate Q203 that depletes the intracellular ATP levels in the bacterium, Mycobacterium tuberculosis. However, single point polymorphism (T313A/I) near the quinol oxidation site of QcrB developed resistance to Q203. In the present study, we analyze the structural changes and drug-resistance mechanism of QcrB due to the point mutation in detail through conformational morphing and molecular docking studies. By morphing, we generated conformers between the open and closed state of the electron transporting cytochrome bc1-aa3 super complex. We clustered them to identify four intermediate structures and relevant intra- and intermolecular motions that may be of functional relevance, especially the binding of Q203 in wild and mutant QcrB intermediate structures and their alteration in developing drug resistance. The difference in the binding score and hydrogen bond interactions between Q203 and the wild-type and mutant intermediate structures of QcrB from molecular docking studies showed that the point mutation T313A severely affected the binding affinity of the candidate drug. Together, the findings provide an in-depth understanding of QcrB inhibition in different conformations, including closed, intermediate, and open states of cytochrome bc1-aa3 super complex in Mycobacterium tuberculosis at the atomic level. We also obtain insights for designing QcrB and cytochrome bc1-aa3 inhibitors as potential therapeutics that may combat drug resistance in tuberculosis.
细胞色素b（QcrB）被认为是电子传递链中的一个必需亚基，它协调整个细胞色素bc1氧化酶的作用。它已被确定为一种有吸引力的药物靶点，针对一种新的有前景的临床候选药物Q203，该药物可消耗结核分枝杆菌细胞内的ATP水平。然而，QcrB喹啉氧化位点附近的单点多态性（T313A/I）对Q203产生了抗性。在本研究中，我们通过构象变形和分子对接研究详细分析了由于点突变导致的QcrB的结构变化和耐药机制。通过变形，我们在电子传递细胞色素bc1-aa3超复合物的开放和关闭状态之间生成了构象异构体。我们对它们进行聚类，以识别四个中间结构以及可能具有功能相关性的相关分子内和分子间运动，特别是Q203在野生型和突变型QcrB中间结构中的结合及其在产生耐药性时的改变。分子对接研究中Q203与QcrB野生型和突变型中间结构之间的结合分数和氢键相互作用的差异表明，点突变T313A严重影响了候选药物的结合亲和力。总之，这些发现提供了对结核分枝杆菌中细胞色素bc1-aa3超复合物在不同构象（包括关闭、中间和开放状态）下QcrB抑制作用的深入原子水平理解。我们还获得了设计QcrB和细胞色素bc1-aa3抑制剂作为潜在治疗药物的见解，这些药物可能对抗结核病中的耐药性。
