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dc.contributor.authorOsteresch, Christin
dc.contributor.authorBender, Tobias
dc.contributor.authorGrond, Stephanie
dc.contributor.authorvon Zezschwitz, Paultheo
dc.contributor.authorKunze, Brigitte
dc.contributor.authorJansen, Rolf
dc.contributor.authorHuss, Markus
dc.contributor.authorWieczorek, Helmut
dc.date.accessioned2012-11-06T13:28:20Z
dc.date.available2012-11-06T13:28:20Z
dc.date.issued2012-09-14
dc.identifier.citationThe Binding Site of the V-ATPase Inhibitor Apicularen Is in the Vicinity of Those for Bafilomycin and Archazolid. 2012, 287 (38):31866-76 J. Biol. Chem.en_GB
dc.identifier.issn1083-351X
dc.identifier.pmid22815478
dc.identifier.doi10.1074/jbc.M112.372169
dc.identifier.urihttp://hdl.handle.net/10033/251212
dc.description.abstractThe investigation of V-ATPases as potential therapeutic drug targets and hence of their specific inhibitors is a promising approach in osteoporosis and cancer treatment because the occurrence of these diseases is interrelated to the function of the V-ATPase. Apicularen belongs to the novel inhibitor family of the benzolactone enamides, which are highly potent but feature the unique characteristic of not inhibiting V-ATPases from fungal sources. In this study we specify, for the first time, the binding site of apicularen within the membrane spanning V(O) complex. By photoaffinity labeling using derivatives of apicularen and of the plecomacrolides bafilomycin and concanamycin, each coupled to (14)C-labeled 4-(3-trifluoromethyldiazirin-3-yl)benzoic acid, we verified that apicularen binds at the interface of the V(O) subunits a and c. The binding site is in the vicinity to those of the plecomacrolides and of the archazolids, a third family of V-ATPase inhibitors. Expression of subunit c homologues from Homo sapiens and Manduca sexta, both species sensitive to benzolactone enamides, in a Saccharomyces cerevisiae strain lacking the corresponding intrinsic gene did not transfer this sensitivity to yeast. Therefore, the binding site of benzolactone enamides cannot be formed exclusively by subunit c. Apparently, subunit a substantially contributes to the binding of the benzolactone enamides.
dc.language.isoenen
dc.rightsArchived with thanks to The Journal of biological chemistryen_GB
dc.titleThe Binding Site of the V-ATPase Inhibitor Apicularen Is in the Vicinity of Those for Bafilomycin and Archazolid.en
dc.typeArticleen
dc.contributor.departmentFrom the Fachbereich Biologie/Chemie, Abteilung Tierphysiologie, Universität Osnabrück, Barbarastrasse 11, 49069 Osnabrück.en_GB
dc.identifier.journalThe Journal of biological chemistryen_GB
refterms.dateFOA2013-09-15T00:00:00Z
html.description.abstractThe investigation of V-ATPases as potential therapeutic drug targets and hence of their specific inhibitors is a promising approach in osteoporosis and cancer treatment because the occurrence of these diseases is interrelated to the function of the V-ATPase. Apicularen belongs to the novel inhibitor family of the benzolactone enamides, which are highly potent but feature the unique characteristic of not inhibiting V-ATPases from fungal sources. In this study we specify, for the first time, the binding site of apicularen within the membrane spanning V(O) complex. By photoaffinity labeling using derivatives of apicularen and of the plecomacrolides bafilomycin and concanamycin, each coupled to (14)C-labeled 4-(3-trifluoromethyldiazirin-3-yl)benzoic acid, we verified that apicularen binds at the interface of the V(O) subunits a and c. The binding site is in the vicinity to those of the plecomacrolides and of the archazolids, a third family of V-ATPase inhibitors. Expression of subunit c homologues from Homo sapiens and Manduca sexta, both species sensitive to benzolactone enamides, in a Saccharomyces cerevisiae strain lacking the corresponding intrinsic gene did not transfer this sensitivity to yeast. Therefore, the binding site of benzolactone enamides cannot be formed exclusively by subunit c. Apparently, subunit a substantially contributes to the binding of the benzolactone enamides.


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