Structure and function of Mycobacterium tuberculosis EfpA as a lipid transporter and its inhibition by BRD-8000.3

• 成果类型: Article
• 署名作者: Li, Delin; Zhang, Xiaokang; Yao, Yuanhang; Sun, Xue; Sun, Junqing; Ma, Xiaomin; Yuan, Kai; Bai, Guijie; Pang, Xuefei; Hua, Rongmao; Guo, Tianling; Mi, Yuqian; Wu, Lingzhi; Zhang, Jie; Wu, Yan; Liu, Yingxia; Wang, Peiyi; Wong, Catherine C. L.; Chen, Xiao-wei; Xiao, Haixia; Gao, George Fu; Gao, Feng
• 署名单位: Chinese Academy of Sciences; Tianjin Institute of Industrial Biotechnology, CAS; Chinese Academy of Sciences; Shenzhen Institute of Advanced Technology, CAS; Peking University; Peking University; Southern University of Science & Technology; Capital Medical University; Southern University of Science & Technology; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College; Peking Union Medical College Hospital; Peking University; Chinese Academy of Sciences; Institute of Microbiology, CAS
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9492
• DOI: 10.1073/pnas.2412653121
• 发表日期: 2024-10-29
• 关键词: polytopic membrane-protein; crystal-structure; gene-expression; TOPOLOGY; mechanism; identification; resistance; responses; encodes; FAMILY

摘要

EfpA, the first major facilitator superfamily (MFS) protein identified in Mycobacterium tuberculosis (Mtb), is an essential efflux pump implicated in resistance to multiple drugs. EfpA- inhibitors have been developed to kill drug- tolerant Mtb. However, the biological function of EfpA has not yet been elucidated. Here, we present the cryo- EM structures of EfpA complexed with lipids or the inhibitor BRD- 8000.3 at resolutions of 2.9 & Aring; and reveal that EfpA is a lipid transporter and BRD- 8000.3 inhibits its lipid transport activthe expression level and oligomeric state of EfpA. Based on our results and the observation of other antiparallel dimers in the MFS family, we propose an antiparallel- function model of EfpA. Collectively, our work provides structural and functional insights into EfpA's role in lipid transport and drug resistance, which would accelerate the development of antibiotics against this promising drug target.