Molecular Basis of CLC Antiporter Inhibition by Fluoride

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  • Maria Gabriella Chiariello, Jülich Research Centre
  • ,
  • Viacheslav Bolnykh, Swiss Federal Institute of Technology Lausanne
  • ,
  • Emiliano Ippoliti, Jülich Research Centre
  • ,
  • Simone Meloni, University of Ferrara
  • ,
  • Jogvan Magnus Haugaard Olsen
  • Thomas Beck, University of Cincinnati
  • ,
  • Ursula Rothlisberger, Swiss Federal Institute of Technology Lausanne
  • ,
  • Christoph Fahlke, Jülich Research Centre
  • ,
  • Paolo Carloni, Jülich Research Centre

CLC channels and transporters conduct or transport various kinds of anions, with the exception of fluoride, which acts as an effective inhibitor. Here, we performed sub-nanosecond DFT-based QM/MM simulations of the E. coli anion/proton exchanger ClC-ec1 and observed that fluoride binds incoming protons within the selectivity filter, with excess protons shared with the gating glutamate E148. Depending on E148 conformation, the competition for the proton can involve either a direct F-/E148 interaction or the modulation of water molecules bridging the two anions. The direct interaction locks E148 in a conformation that does not allow for proton transport, and thus inhibits protein function.

TidsskriftJournal of the American Chemical Society
Sider (fra-til)7254-7258
Antal sider5
StatusUdgivet - 22 apr. 2020
Eksternt udgivetJa

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