The Binding Site of the V-ATPase Inhibitor Apicularen Is in the Vicinity of Those for Bafilomycin and Archazolid
The Binding Site of the V-ATPase Inhibitor Apicularen Is in the Vicinity of Those for Bafilomycin and Archazolid
复制标题
V-ATP 酶抑制剂 Apicalen 的结合位点位于 Bafilomycin 和 Archazolid 的结合位点附近
DOI：
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发表时间：
2012
影响因子：
4.8
通讯作者：
H. Wieczorek
中科院分区：
文献类型：
--
作者：
Christin Osteresch;Tobias Bender;S. Grond;Paultheo von Zezschwitz;B. Kunze;R. Jansen;M. Huss;H. Wieczorek
背景：Apicularen是一种特异性的V-ATP酶抑制剂，与全酶的VO复合物结合。结果：Apicularen与VO亚基a和c结合。结论：apicularen的结合位点与巴夫洛霉素和archazolid的结合位点相近。意义：我们提出了这三类V-ATP酶抑制剂结合位点排列的第一个模型。研究V-ATP酶作为潜在的治疗药物靶点及其特异性抑制剂在骨质疏松症和癌症治疗中是一种有前途的方法，因为这些疾病的发生与V-ATP酶的功能相关。Apicularen属于苯内酯烯酰胺的新型抑制剂家族，其具有高度有效性，但具有不抑制来自真菌来源的V-ATP酶的独特特征。在这项研究中，我们指定，第一次，apicularen跨膜VO复合物内的结合位点。通过使用apicularen和plecomacrolides巴夫洛霉素和康卡霉素的衍生物进行光亲和标记，每个衍生物与14 C标记的4-（3-三氟甲基二氮杂环丙烯-3-基）苯甲酸偶联，我们验证了apicularen在VO亚基a和c的界面处结合。结合位点在plecomacrolides和archazolids（第三个V-ATP酶抑制剂家族）的结合位点附近。从智人和烟草天蛾，这两个物种敏感的苯内酯酰胺，在酿酒酵母菌株缺乏相应的内在基因的亚基c同系物的表达没有转移到酵母的敏感性。因此，苯内酯酰胺的结合位点不能仅由亚基c形成。显然，亚基a实质上有助于苯并内酯酰胺的结合。
Background: Apicularen is a specific V-ATPase inhibitor that binds to the VO complex of the holoenzyme. Results: Apicularen binds at the interface of the VO subunits a and c. Conclusion: The binding site for apicularen is in the vicinity of those for bafilomycin and archazolid. Significance: We propose the first model of binding site arrangement for these three classes of V-ATPase inhibitors. 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 VO complex. By photoaffinity labeling using derivatives of apicularen and of the plecomacrolides bafilomycin and concanamycin, each coupled to 14C-labeled 4-(3-trifluoromethyldiazirin-3-yl)benzoic acid, we verified that apicularen binds at the interface of the VO 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.
影响因子：
2.9
作者：
Toei, Masashi;Saum, Regina;Forgac, Michael
通讯作者：
Forgac, Michael
DOI：
10.1073/pnas.85.21.7972
发表时间：
1988-11-01
影响因子：
11.1
作者：
BOWMAN, EJ;SIEBERS, A;ALTENDORF, K
通讯作者：
ALTENDORF, K
影响因子：
5.6
作者：
Muench, Stephen P.;Huss, Markus;Harrison, Michael A.
通讯作者：
Harrison, Michael A.