Structure-Based Identification of the Binding Site for the Hemiasterlin Analogue HTI-286 on Tubulin

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• 作者：Malini Ravi ; Arie Zask ; and Thomas S. Rush III
• 刊名：Biochemistry
• 出版年：2005
• 出版时间：December 6, 2005
• 年：2005
• 卷：44
• 期：48
• 页码：15871 - 15879
• 全文大小：395K
• 年卷期：v.44,no.48(December 6, 2005)
• ISSN：1520-4995

文摘

A binding mode of HTI-286, a synthetic analogue of the peptidic antimitotic agent hemiasterlin,to tubulin is proposed. The binding mode was derived from iterative docking experiments directed atregions of the tubulin interdimer interface that are believed to be consistent with all current experimentaldata regarding the HTI-286/tubulin interaction. These data include (1) competitive inhibition of the tubulinbinding of the Vinca alkaloids and other antimitotic agents, (2) proximity to stretches of amino acidresidues identified in two separate photoaffinity-labeling experiments, (3) structure-activity relationshipsfor HTI-286 and its analogues, (4) saturation transfer difference nuclear magnetic resonance (NMR)experiments, and (5) NMR transfer nuclear Overhauser effect spectroscopy (NOESY) experiments thatpotentially identify the bioactive conformation. The predicted binding mode thus affords a means tounderstand the mode of action of hemiasterlin, HTI-286, and other closely related molecules.