Sackett D L
Laboratory of Biochemical Pharmacology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Biochemistry. 1995 May 30;34(21):7010-9. doi: 10.1021/bi00021a012.
Vinca site agents are antimicrotubule compounds that bind to the same site on tubulin as do the vinca alkaloids. These include agents that induce the formation of nonmicrotubule oligomers of tubulin (vinblastine and vincristine) and agents that do not (maytansine and rhizoxin). All of these quench the fluorescence of tubulin upon binding. Quenching preferentially affects the red side of tubulin emission, likely affecting more than one solvent-exposed tryptophan. Similar quenching is observed upon binding to either tubulin or tubulin-colchicine. None of these agents induces the local unfolding of the amphipathic helix in the carboxyl terminal region of beta-tubulin that colchicine and other colchicine site ligands do. All four vinca site agents inhibit this unfolding in tubulin-colchicine complexes without displacing colchicine. Both groups of vinca site agents enhance the chymotryptic cleavage of beta-tubulin after Tyr-281. Both groups of vinca site agents increase the beta-tubulin specificity of photolabeling with colchicine, and both groups inhibit colchicine-stimulated GTP hydrolysis. All of these effects common to both groups of vinca site agents are interpreted as due to vinca site occupancy alone. The vinca alkaloids differ from maytansine and rhizoxin by causing a large enhancement of chymotryptic cleavage of beta and a large inhibition of typtic cleavage of alpha, after Arg-339. These effects are interpreted as due to vinca induced oligomerization of tubulin. It is argued that the common binding site for the vinca site agents is located on beta-tubulin, close to the helix that is disrupted by colchicine.
长春花属位点药物是抗微管化合物，它们与微管蛋白上的位点结合，就如同长春花生物碱那样。这些药物包括诱导微管蛋白形成非微管寡聚体的药物（长春碱和长春新碱）以及不诱导的药物（美登素和根霉素）。所有这些药物在结合时都会淬灭微管蛋白的荧光。淬灭优先影响微管蛋白发射的红色部分，可能影响不止一个暴露于溶剂中的色氨酸。在与微管蛋白或微管蛋白 - 秋水仙碱结合时都观察到类似的淬灭现象。这些药物都不会像秋水仙碱和其他秋水仙碱位点配体那样诱导β - 微管蛋白羧基末端区域两亲性螺旋的局部展开。所有四种长春花属位点药物都能抑制微管蛋白 - 秋水仙碱复合物中的这种展开，而不会取代秋水仙碱。两组长春花属位点药物都能增强酪氨酸 - 281 之后β - 微管蛋白的胰凝乳蛋白酶切割。两组长春花属位点药物都能增加秋水仙碱光标记的β - 微管蛋白特异性，并且两组都能抑制秋水仙碱刺激的 GTP 水解。长春花属位点药物两组共有的所有这些效应都被解释为仅仅是由于长春花属位点被占据。长春花生物碱与美登素和根霉素不同，它们会导致β在精氨酸 - 339 之后胰凝乳蛋白酶切割的大幅增强以及α胰蛋白酶切割的大幅抑制。这些效应被解释为是由于长春花诱导的微管蛋白寡聚化。有人认为长春花属位点药物的共同结合位点位于β - 微管蛋白上，靠近被秋水仙碱破坏的螺旋。
