主講人：楊海濤 研究員（上?？萍即髮W(xué)）

　　時(shí)間：2019年7月5日 11:00-12:00am 

　　地點(diǎn)：廣州生物醫(yī)藥與健康研究院（A326）

　　主持人：何俊 研究員

　　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.

　　楊海濤研究員長期從事寨卡病毒，結(jié)核分枝桿菌等重要病原體引發(fā)的重大疾病的研究，并針對(duì)性的開展全新藥物開發(fā)工作。擔(dān)任國家重點(diǎn)基礎(chǔ)研究發(fā)展計(jì)劃（973計(jì)劃）青年項(xiàng)目首席科學(xué)家、國家重點(diǎn)研發(fā)計(jì)劃責(zé)任專家、國家“重大新藥創(chuàng)制”科技重大專項(xiàng)評(píng)審專家、長江學(xué)者獎(jiǎng)勵(lì)計(jì)劃評(píng)審專家、波蘭國家科學(xué)基金外審專家。