Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300353, China.
Proc Natl Acad Sci U S A. 2021 Apr 13;118(15). doi: 10.1073/pnas.2022308118.
Complex II, also known as succinate dehydrogenase (SQR) or fumarate reductase (QFR), is an enzyme involved in both the Krebs cycle and oxidative phosphorylation. Mycobacterial Sdh1 has recently been identified as a new class of respiratory complex II (type F) but with an unknown electron transfer mechanism. Here, using cryoelectron microscopy, we have determined the structure of Sdh1 in the presence and absence of the substrate, ubiquinone-1, at 2.53-Å and 2.88-Å resolution, respectively. Sdh1 comprises three subunits, two that are water soluble, SdhA and SdhB, and one that is membrane spanning, SdhC. Within these subunits we identified a quinone-binding site and a rarely observed Rieske-type [2Fe-2S] cluster, the latter being embedded in the transmembrane region. A mutant, where two His ligands of the Rieske-type [2Fe-2S] were changed to alanine, abolished the quinone reduction activity of the Sdh1. Our structures allow the proposal of an electron transfer pathway that connects the substrate-binding and quinone-binding sites. Given the unique features of Sdh1 and its essential role in , these structures will facilitate antituberculosis drug discovery efforts that specifically target this complex.
复合物 II，也称为琥珀酸脱氢酶（SQR）或延胡索酸还原酶（QFR），是参与克雷布斯循环和氧化磷酸化的酶。分枝杆菌 Sdh1 最近被鉴定为一种新型呼吸复合物 II（F 型），但其电子转移机制尚不清楚。在这里，我们使用冷冻电子显微镜，分别在存在和不存在底物泛醌-1 的情况下，以 2.53-Å 和 2.88-Å 的分辨率确定了 Sdh1 的结构。Sdh1 由三个亚基组成，两个是水溶性的 SdhA 和 SdhB，一个是跨膜的 SdhC。在这些亚基中，我们鉴定了一个醌结合位点和一个罕见的 Rieske 型 [2Fe-2S] 簇，后者嵌入跨膜区域。将 Rieske 型 [2Fe-2S] 的两个 His 配体突变为丙氨酸的突变体，使 Sdh1 的醌还原活性丧失。我们的结构允许提出一个电子传递途径，该途径连接底物结合和醌结合位点。鉴于 Sdh1 的独特特征及其在中的重要作用，这些结构将促进专门针对该复合物的抗结核药物发现工作。
