Seminar Colour Guide:              
Hamburg Speaker
Friday, 27 April 2018, 13:00Add to calendar"Anomalous SAXS at P12 beamline EMBL Hamburg"Andrey Gruzinov, EMBL Hamburg Unit, GermanyHost: Dmitri SvergunSeminar Room 48e, EMBL Hamburg
Hamburg Speaker
Friday, 4 May 2018, 13:00Add to calendarStructure of the Mycobacterial Type VII Secretion SystemKate Beckham, EMBL Hamburg Unit, GermanyHost: Matthias WilmannsSeminar Room 48e, EMBL Hamburg
Hamburg Speaker
Friday, 18 May 2018, 13:00Add to calendarModel-building challenges for crystallographic maps at low-resolution
Grzegorz Chojnowski, EMBL Hamburg Unit, GermanyHost: Victor LamzinSeminar Room 48e, EMBL Hamburg
Hamburg Speaker
Friday, 25 May 2018, 13:00Add to calendarVariations of subunit α, γ and ε of the Mycobacterium tuberculosis F-ATP synthase cause structural, mechanistic and enzymatic alterations, leading to the design of novel TB compoundsGerhard Grueber, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 639798 Singapore, SingaporeHost: Dmitri SvergunSeminar Room 48e, EMBL Hamburg
Abstract: With one-third of mankind infected subclinically, an incidence of nine million new cases of active tuberculosis disease (TB) and two million deaths per year, Mycobacterium tuberculosis, remains the most important bacterial pathogen in the world [1]. This enzyme complex is composed of nine subunits in the stoichiometry of α3:β3:γ:δ:ε:a:b:b :c9, and organized in a membrane-embedded FO domain (a:b:b :c9-12) and a water soluble F1 part (α3:β3:γ:δ:ε:). Mycobacterial F-ATP synthase has been shown to be essential for growth and survival, which is different from other prokaryotes, where the enzyme is dispensable for growth on fermentable carbon sources and where increased glycolytic flux can compensate for the loss of oxidative phosphorylation [2]. Another special feature of the mycobacterial F-ATP synthase is its inability to establish a significant proton gradient during ATP hydrolysis, and its low or latent ATPase activity in the fast- or slow-growing form [3-4].
The presentation reveals that at least the three subunits α, γ and ε contribute to the important enzymatic differences of mycobacterial F-ATP synthases in suppression of proton pumping and proton motive force (PMF) formation [4-6], which is essential because dissipating the PMF is lethal to mycobacteria, as well as in ATP formation, employing them as potential drug targets. Our novel atomic structure of the rotating subunit ε in solution provides insights into a new mechanism of coupling proton-conduction with ATP synthesis and identifies a second binding site of the TB drug bedaquiline (BDQ, Sirturo®) [6].
Using a combination of recombineering, ensemble and single molecule assays, solution X-ray scattering, NMR spectroscopy and electron microscopy it will be shown that unique mycobacterial stretches inside the nucleotide-binding subunit α and γ influence cell growth, ATPase activity and ATP synthesis of the pathogen [4-5].
These data formed a platform to identify and synthesize new compounds, which effectively inhibit ATPase and ATP synthesis of mycrobacterial F-ATP synthase and inhibit growth of Mycobacterium smegmatis, M. bovis as well as M. tuberculosis.
References
1. World Health Organization (2014) Global Tuberculosis Report 2014, 1-171
2. Cook, G.M., Hards, K., Vilcheze, C., Hartman, T. & Berney, M. (2014) Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria. Microbiol. Spectr. 2, doi:10.1128/microbiolspec.MGM2-0015-2013.
3. Haagsma, A.C., Driessen, N.N., Hahn, M.M., Lill, H. & Bald, D. (2010) ATP synthase in slow- and fast-growing mycobacteria is active in ATP synthesis and blocked in ATP hydrolysis direction. FEMS Microbiol. Lett. 313, 68-74.
4. Hotra, A., Suter, M., Biuković, G., Ragunathan, P., Kundu, S. Dick, T. & Grüber, G. (2016) Deletion of a unique loop in the mycobacterial F-ATP synthase gamma subunit sheds light on its inhibitory role in ATP hydrolysis-driven H(+) pumping. FEBS J. 283, 1947-1961.
5. Ragunathan, P., Sielaff, H., Sundararaman, L., Biuković, G., Manimekalai, M.S.S., Singh, D., Kundu, S., Wohland, T., Frasch, W., Dick, T. & Grüber, G. (2017) The uniqueness of subunit α of mycobacterial F-ATP synthases: An evolutionary variant for niche adaptation. J. Biol. Chem. 292, 11262-11279.
6. Shin, J., Ragunathan, P., Sundararaman, L., Nartey, W., Kundu, S., Manimekalai, M.S.S., Bogdanović, N., Dick, T. & Grüber, G. (2018) The NMR solution structure of Mycob
External Faculty Speaker
Friday, 1 June 2018, 13:00Add to calendarThe RNA synthesis machine of influenza viruses and innate immune sensingErvin Fodor, University of Oxford, United KingdomHost: Jan KosinskiSeminar Room 48e, EMBL Hamburg
Abstract: tbd
Hamburg Speaker
Monday, 11 June 2018, 13:00Add to calendarNot all organelles were created equal - uncovering the mechanism defining a lipid droplet subpopulationMaja Schuldiner, Weizmann Institute, Rehovot, IsraelHost: Matthias WilmannsSeminar Room 48e
Hamburg Speaker
Friday, 15 June 2018, 13:00Add to calendar"Substrate promiscuity and drug uptake in proton dependent oligo-peptide transporters"
Christian Loew, EMBL, Hamburg Unit, GermanyHost: Christian LoewSeminar Room 48e, EMBL Hamburg
Hamburg Speaker
Friday, 6 July 2018, 13:00Add to calendarAttacking the membrane with SAXSHaydyn Mertens, EMBL, Hamburg Unit, GermanyHost: Dmitri SvergunSeminar Room 48e, EMBL Hamburg
Hamburg Speaker
Friday, 13 July 2018, 13:00Add to calendarStructural characterisation of the von Willebrand factorEmma Ruoqi Xu, EMBL, Hamburg Unit, GermanyHost: Matthias WilmannsSeminar Room 48e, EMBL Hamburg
Hamburg Speaker
Friday, 27 July 2018, 13:00Add to calendartbdRhys Grinter, Lithgow Laboratory, Monash University, AustraliaHost: Matthias WilmannsSeminar Room 48e