The Natural Resistance-Associated Macrophage Protein (Nramp) family of secondary active divalent metal ion transporters plays an important role in a variety of biological processes, such as metal ion homeostasis, in virtually all living organisms. Due to its structural and functional homology with eukaryotic Nramps, the E. coli transporter MntH (Proton-dependent Manganese Transporter) represents a prototypic model to advance understanding of structure-function relationship in Nramp family. Synthetic peptides corresponding to the transmembrane (TM) segments of membrane proteins could serve as a suitable alternative model for studying the structure and interaction of the membrane protein TM domains with biological membranes. In this study the synthetic peptide corresponding to the sixth transmembrane segment (TMS6) of E. coli MntH and its two mutants, in which the His211 residue was substituted by arginine or alanine, were used. TMS6 was previously shown to contain two functionally important histidine residues. The H211A mutation preserves bacterial sensitivity to metal ions and facilitate H+ uptake in the presence of metal ions. In contrast, H211R does not induce metal sensitivity (1,2). The secondary structures of TMS6 and its mutants were determined in model membranes and membrane-mimicking organic environments, using CD spectroscopy. The conformation of the peptides exhibited ordered α and β conformations in these milieus. Furthermore, patch clamp measurements demonstrated that TMS6 was able to form multi-state ion channels in the presence of manganese as a physiological substrate of MntH. The mutant H211R does not show any channel-like activity and with the mutant H211A the ion channel activity was rarely observed.1. Lam-Yuk-Tseung, S., Govoni, G., Forbes, J., and Gros, P. (2003) Blood 101, 3699-3707.2. Chaloupka, R., Courville, P., Veyrier, F., Knudsen, B., Tompkins, T.A., and Cellier, M.F. (2005) Biochemistry 44, 726-733.