The Binding Site of the V-ATPase Inhibitor Apicularen Is in the Vicinity of Those for Bafilomycin and Archazolid

Autor(en): Osteresch, Christin
Bender, Tobias
Grond, Stephanie
von Zezschwitz, Paultheo
Kunze, Brigitte
Jansen, Rolf
Huss, Markus 
Wieczorek, Helmut 
Stichwörter: 16-KDA PROTEOLIPID SUBUNIT; Biochemistry & Molecular Biology; CHONDROMYCES-SPECIES MYXOBACTERIA; CONCANAMYCIN-A; DISSOCIATION; MANDUCA-SEXTA; MEMBRANE; O-SUBUNIT; PROTON-TRANSLOCATING ATPASE; PURIFICATION; VACUOLAR H+-ATPASE
Erscheinungsdatum: 2012
Herausgeber: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Enthalten in: JOURNAL OF BIOLOGICAL CHEMISTRY
Band: 287
Ausgabe: 38
Startseite: 31866
Seitenende: 31876
Zusammenfassung: 
The 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 C-14-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.
ISSN: 00219258
DOI: 10.1074/jbc.M112.372169

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