Molecular Basis of CLC Antiporter Inhibition by Fluoride

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.


Published in:
Journal Of The American Chemical Society, 142, 16, 7254-7258
Year:
Apr 22 2020
Publisher:
Washington, AMER CHEMICAL SOC
ISSN:
0002-7863
1520-5126
Keywords:
Laboratories:




 Record created 2020-05-14, last modified 2020-05-15


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