title: Predicted Structures of the Proton-Bound Membrane-Embedded Rotor Rings of the Saccharomyces cerevisiae and Escherichia coli ATP Synthases.
abstract: Recent years have witnessed a renewed interest in the ATP synthase as a drug target against human pathogens. Indeed, clinical, biochemical, and structural data indicate that hydrophobic inhibitors targeting the membrane-embedded proton-binding sites of the c-subunit ring could serve as last-resort antibiotics against multidrug resistant strains. However, because inhibition of the mitochondrial ATP synthase in humans is lethal, it is essential that these inhibitors be not only potent but also highly selective for the bacterial enzyme. To this end, a detailed understanding of the structure of this protein target is arguably instrumental. Here, we use computational methods to predict the atomic structures of the proton-binding sites in two prototypical c-rings: that of the ATP synthase from Saccharomyces cerevisiae, which is a model system for mitochondrial enzymes, and that from Escherichia coli, which can be pathogenic for humans. Our study reveals the structure of these binding sites loaded with protons and in the context of the membrane, that is, in the state that would mediate the recognition of a potential inhibitor. Both structures reflect a mode of proton coordination unlike those previously observed in other c-ring structures, whether experimental or modeled.
authors.affiliation: Theoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Wenchang
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Theoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Leone
authors.affiliation: Theoretical Molecular Biophysics Group, Max Planck Institute of Biophysics , 60438 Frankfurt am Main, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Krah
authors.affiliation: Theoretical Molecular Biophysics Section, National Heart, Lung and Blood Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.|Theoretical Molecular Biophysics Group, Max Planck Institute of Biophysics , 60438 Frankfurt am Main, Germany.
authors.forename: José D
authors.initials: JD
authors.lastname: Faraldo-Gómez
mesh_terms: D004926:Escherichia coli / Q000201:enzymology*; D008958:Models, Molecular; D011487:Protein Conformation; D006180:Proton-Translocating ATPases / Q000737:chemistry* / Q000378:metabolism; D011522:Protons; D012441:Saccharomyces cerevisiae / Q000201:enzymology*
chemical_list: D011522:Protons; D006180:Proton-Translocating ATPases