Cryo-EM structure of trimeric Mycobacterium smegmatis succinate dehydrogenase with a membrane-anchor SdhF

• Published in: Nature communications Vol. 11; no. 1; p. 4245
• Main Authors: Gong, Hongri, Gao, Yan, Zhou, Xiaoting, Xiao, Yu, Wang, Weiwei, Tang, Yanting, Zhou, Shan, Zhang, Yuying, Ji, Wenxin, Yu, Lu, Tian, Changlin, Lam, Sin Man, Shui, Guanghou, Guddat, Luke W., Wong, Luet-Lok, Wang, Quan, Rao, Zihe
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.08.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 631/154; 631/326; 631/45/535/1258/1259; 631/57; Bacteria; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Binding Sites; Catalysis; Cryoelectron Microscopy; Drug development; Electron microscopy; Electron Transport; Gram-positive bacteria; Humanities and Social Sciences; Membranes; Menaquinones; Models, Molecular; multidisciplinary; Multienzyme Complexes - chemistry; Multienzyme Complexes - genetics; Multienzyme Complexes - metabolism; Mycobacterium smegmatis; Mycobacterium smegmatis - chemistry; Mycobacterium smegmatis - enzymology; Oxidation; Oxidation-Reduction; Protein Subunits - chemistry; Protein Subunits - metabolism; Protons; Quinones; Science; Science (multidisciplinary); Structure-Activity Relationship; Succinate dehydrogenase; Succinate Dehydrogenase - chemistry; Succinate Dehydrogenase - metabolism; Succinic Acid - metabolism; Trimers; Vitamin K 2 - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-18011-9

Diheme-containing succinate:menaquinone oxidoreductases (Sdh) are widespread in Gram-positive bacteria but little is known about the catalytic mechanisms they employ for succinate oxidation by menaquinone. Here, we present the 2.8 Å cryo-electron microscopy structure of a Mycobacterium smegmatis Sdh, which forms a trimer. We identified the membrane-anchored SdhF as a subunit of the complex. The 3 kDa SdhF forms a single transmembrane helix and this helix plays a role in blocking the canonically proximal quinone-binding site. We also identified two distal quinone-binding sites with bound quinones. One distal binding site is formed by neighboring subunits of the complex. Our structure further reveals the electron/proton transfer pathway for succinate oxidation by menaquinone. Moreover, this study provides further structural insights into the physiological significance of a trimeric respiratory complex II. The structure of the menaquinone binding site could provide a framework for the development of Sdh-selective anti-mycobacterial drugs. Diheme-containing succinate:menaquinone oxidoreductases (Sdh) are members of the complex II superfamily. Here, the authors present the 2.8 Å cryo-EM structure of Mycobacterium smegmatis Sdh2, which reveals membrane-anchored SdhF as a component of the complex and they discuss the electron/proton transfer pathway in the Sdh2 trimer.