title: Restored Physiology in Protein-Deficient Yeast by a Small Molecule Channel.
abstract: Deficiencies of protein ion channels underlie many currently incurable human diseases. Robust networks of pumps and channels are usually responsible for the directional movement of specific ions in organisms ranging from microbes to humans. We thus questioned whether minimally selective small molecule mimics of missing protein channels might be capable of collaborating with the corresponding protein ion pumps to restore physiology. Here we report vigorous and sustainable restoration of yeast cell growth by replacing missing protein ion transporters with imperfect small molecule mimics. We further provide evidence that this tolerance for imperfect mimicry is attributable to collaboration between the channel-forming small molecule and protein ion pumps. These results illuminate a mechanistic framework for pursuing small molecule replacements for deficient protein ion channels that underlie a range of challenging human diseases.
authors.affiliation: †Howard Hughes Medical Institute and ‡Departments of Biochemistry and §Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Cioffi
authors.affiliation: †Howard Hughes Medical Institute and ‡Departments of Biochemistry and §Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hou
authors.affiliation: †Howard Hughes Medical Institute and ‡Departments of Biochemistry and §Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Grillo
authors.affiliation: †Howard Hughes Medical Institute and ‡Departments of Biochemistry and §Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
authors.forename: Katrina A
authors.initials: KA
authors.lastname: Diaz
authors.affiliation: †Howard Hughes Medical Institute and ‡Departments of Biochemistry and §Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Burke
mesh_terms: D000666:Amphotericin B / Q000737:chemistry* / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D007473:Ion Channels / Q000737:chemistry / Q000378:metabolism; D054833:Isoindoles; D018716:Molecular Mimicry; D009154:Mutation; D016566:Organoselenium Compounds / Q000494:pharmacology; D006180:Proton-Translocating ATPases / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D001393:Azoles; D027682:Cation Transport Proteins; D007473:Ion Channels; D054833:Isoindoles; D016566:Organoselenium Compounds; D029701:Saccharomyces cerevisiae Proteins; C085258:TRK2 protein, S cerevisiae; C068664:TRK1 protein, S cerevisiae; C042986:ebselen; D000666:Amphotericin B; C092477:PMA1 protein, S cerevisiae; D006180:Proton-Translocating ATPases