主讲人：杨海涛 研究员（上海科技大学）

　　时间：2019年7月5日 11:00-12:00am 

　　地点：广州生物医药与健康研究院（A326）

　　主持人：何俊 研究员

　　Despite intensive efforts to discover highly effective treatments to eradicate tuberculosis (TB), it remains as a major threat to global human health. For this reason, new TB drugs directed towards new targets are highly coveted.

　　MmpLs (Mycobacterial membrane proteins Large) which play crucial roles in transporting lipids, polymers and immunomodulators, and that also extrude therapeutic drugs, are amongst the most important therapeutic drug targets to emerge in recent times. Here, crystal structures of Mycobacterial MmpL3 alone and in complex with four TB drug candidates including SQ109 (in Phase 2b-3 clinical trials) are reported. MmpL3 consists of a periplasmic pore domain and a twelve-helix transmembrane domain. Two Asp-Tyr pairs centrally located in this domain appear to be key facilitators of proton-translocation. SQ109, AU1235 and ICA38 bind inside the transmembrane region and disrupt these Asp-Tyr pairs. Strikingly, rimonabant, the first CB1 antagonist, was also found to target the same binding pocket. It is remarkable that rimonabant adopts completely different binding modes to inhibit mycobacterial MmpL3 and human CB1 receptor. Since MmpL3 and its orthologues are well conserved across mycobacteria and corynebacteria, these results may facilitate the development of new drugs which are broadly effective against these and other human pathogenic infectious diseases including TB, leprosy and diphtheria. In addition, this is the first report describing structures of drug candidates which can block the proton motive force to inhibit an RND family member, many of which are important targets for anti-bacterial drug discovery. These data will therefore provide inspiration for the design of new classes of antibiotics.

　　杨海涛研究员长期从事寨卡病毒，结核分枝杆菌等重要病原体引发的重大疾病的研究，并针对性的开展全新药物开发工作。担任国家重点基础研究发展计划（973计划）青年项目首席科学家、国家重点研发计划责任专家、国家“重大新药创制”科技重大专项评审专家、长江学者奖励计划评审专家、波兰国家科学基金外审专家。