2.A.36.6.5
K⁺:H⁺ antiporter NhaP2 (catalyzes K⁺:H⁺ and Na⁺:H⁺ exchange; Resch et al., 2010). (84% identical to 2.A.36.6.3). A cation binding pocket in the middle of the membrane and a pathway leading to it have been identified (Mourin et al. 2018). There are 3 NhaP types in Vibrio cholerae (Vc-NhaP1, 2, and 3).  They are critical for maintenance of K⁺ homeostasis in the cytoplasm, and all 3 are required for cell survival at low pHs, suggesting a role in acid tolerance (Mourin et al. 2019). The solution structure of the N-terminal cytoplasmic domain of ~200 aas has been solved (Orriss et al. 2020). It reveals a compact N-terminal domain which resembles a Regulator of Conductance of K⁺ channels (RCK) domain connected to a more open C-terminal domain via a flexible 20 amino acid linker. NMR titration experiments showed that the protein binds ATP through its N-terminal domain (Orriss et al. 2020). Modified amiloride analogs with promising binding properties have been developed. Four selected drugs interacted with functionally important amino acid residues located on the cytoplasmic side of TMS VI, the extended chain region of TMSs V and XII, and the loop region between TMSs VIIII and IX (Mourin et al. 2021).