Predicted Structures of the Proton-Bound Membrane-Embedded Rotor Rings of the Saccharomyces cerevisiae and Escherichia coli ATP Synthases. J Phys Chem B 2017 Apr 20;121(15):3297-3307
Date
11/04/2016Pubmed ID
27715045Pubmed Central ID
PMC5593136DOI
10.1021/acs.jpcb.6b08051Scopus ID
2-s2.0-85020184139 (requires institutional sign-in at Scopus site) 7 CitationsAbstract
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.
Author List
Zhou W, Leone V, Krah A, Faraldo-Gómez JDAuthor
Vanessa Leone PhD Assistant Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Escherichia coliModels, Molecular
Protein Conformation
Proton-Translocating ATPases
Protons
Saccharomyces cerevisiae
