1.A.72.1.1

The MerF mercuric ion uptake transporter of 81 aas and 2 TMSs. The NMR structure of the helix-loop-helix core domain of MerF has been determined with a backbone RMSD of 0.58 Å (Howell et al. 2005). Moreover, the fold of this polypeptide demonstrates that the two vicinal pairs of cysteine residues, shown to be involved in the transport of Hg⁺⁺ across the membrane, are exposed to the cytoplasm. This finding differs from earlier structural and mechanistic models that were based primarily on the somewhat atypical hydropathy plot for MerF and related transport proteins (Howell et al. 2005). The apo state positions one of the cysteine pairs closer to the periplasmic side of the membrane, while in the bound state, the same pair approaches the cytoplasmic side (Hwang et al. 2019). This is consistent with the functional requirement of accepting Hg²⁺ from the periplasmic space, sequestering it on acceptance, and transferring it to the cytoplasm. Conformational changes in the TMSs facilitate the functional interaction of the two cysteine pairs. Free-energy calculations provide a barrier of 16 kcal/mol for the association of the periplasmic Hg²⁺-bound protein, MerP, with MerF, and 7 kcal/mol for the subsequent association of MerF's two cysteine pairs (Hwang et al. 2019).