Psoromic Acid is a Selective and Covalent Rab-Prenylation Inhibitor Targeting Autoinhibited RabGGTase
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- 作者：C茅line Deraeve ; Zhong Guo ; Robin S. Bon ; Wulf Blankenfeldt ; Raffaella DiLucrezia ; Alexander Wolf ; Sascha Menninger ; E. Anouk Stigter ; Stefan Wetzel ; Axel Choidas ; Kirill Alexandrov ; Herbert Waldmann ; Roger S. Goody ; Yao-Wen Wu
- 刊名：The Journal of the American Chemical Society
- 出版年：2012
- 出版时间：May 2, 2012
- 年：2012
- 卷：134
- 期：17
- 页码：7384-7391
- 全文大小：423K
- 年卷期：v.134,no.17(May 2, 2012)
- ISSN：1520-5126
文摘
Post-translational attachment of geranylgeranyl isoprenoids to Rab GTPases, the key organizers of intracellular vesicular transport, is essential for their function. Rab geranylgeranyl transferase (RabGGTase) is responsible for prenylation of Rab proteins. Recently, RabGGTase inhibitors have been proposed to be potential therapeutics for treatment of cancer and osteoporosis. However, the development of RabGGTase selective inhibitors is complicated by its structural and functional similarity to other protein prenyltransferases. Herein we report identification of the natural product psoromic acid (PA) that potently and selectively inhibits RabGGTase with an IC50 of 1.3 渭M. Structure鈥揳ctivity relationship analysis suggested a minimal structure involving the depsidone core with a 3-hydroxyl and 4-aldehyde motif for binding to RabGGTase. Analysis of the crystal structure of the RabGGTase:PA complex revealed that PA forms largely hydrophobic interactions with the isoprenoid binding site of RabGGTase and that it attaches covalently to the N-terminus of the 伪 subunit. We found that in contrast to other protein prenyltransferases, RabGGTase is autoinhibited through N-terminal 伪His2 coordination with the catalytic zinc ion. Mutation of 伪His dramatically enhances the reaction rate, indicating that the activity of RabGGTase is likely regulated in vivo. The covalent binding of PA to the N-terminus of the RabGGTase 伪 subunit seems to potentiate its interaction with the active site and explains the selectivity of PA for RabGGTase. Therefore, psoromic acid provides a new starting point for the development of selective RabGGTase inhibitors.