Distinct pose of discodermolide in taxol binding pocket drives a complementary mode of microtubule stabilization.
Distinct pose of discodermolide in taxol binding pocket drives a complementary mode of microtubule stabilization.
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DOI：
10.1021/bi901351q
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发表时间：
2009-12-15
期刊：
影响因子：
2.9
通讯作者：
Xiao, Hui
中科院分区：
文献类型：
--
作者：
Khrapunovich-Baine, Marina;Menon, Vilas;Verdier-Pinard, Pascal;Smith, Amos B., III;Angeletti, Ruth Hogue;Fiser, Andras;Horwitz, Susan Band;Xiao, Hui
微管细胞骨架已被证明是癌症治疗的有效靶点。一类药物被称为微管稳定剂（MSA），它与微管聚合物结合并稳定它们以防止解聚。该组药物的原型紫杉醇是一种有效的化疗药物，广泛用于治疗人类卵巢癌、乳腺癌和肺癌。尽管电子晶体学和光亲和标记实验确定紫杉醇的结合位点位于β-微管蛋白的疏水口袋中，但人们对该药物对整个微管构象的影响知之甚少。我们实验室最近的一项研究利用氢-氘交换 (HDX) 与各种质谱 (MS) 技术相结合，提供了有关紫杉醇结合时微管结构的新信息。在当前的研究中，我们应用该技术来确定另一种MSAdiscodermolide的结合模式和对鸡红细胞微管蛋白（CET）的构象影响，其合成类似物可能在临床中具有潜在用途。我们证实，与紫杉醇一样，discodermolide 与 β-微管蛋白中的紫杉烷结合袋结合。然而，与与 M 环有主要相互作用的紫杉醇相反，discodermolide 使其自身远离该环并朝向 N 末端 H1-S2 环。此外，discodermolide 主要通过其对二聚体间接触的影响，特别是在 α-微管蛋白一侧，以及在较小程度上对相邻 β-微管蛋白亚基之间的原丝间接触的影响来稳定微管。此外，我们的结果表明紫杉醇和 discodermolide 对微管具有互补的稳定作用，这可能解释了两种药物在体内观察到的协同作用。
The microtubule cytoskeleton has proven to be an effective target for cancer therapeutics. One class of drugs, known as microtubule stabilizing agents (MSAs), binds to microtubule polymers and stabilizes them against depolymerization. The prototype of this group of drugs, Taxol, is an effective chemotherapeutic agent used extensively in the treatment of human ovarian, breast, and lung carcinomas. Although electron crystallography and photoaffinity labeling experiments determined that the binding site for Taxol is in a hydrophobic pocket in β-tubulin, little was known about the effects of this drug on the conformation of the entire microtubule. A recent study from our laboratory utilizing hydrogen-deuterium exchange (HDX) in concert with various mass spectrometry (MS) techniques has provided new information on the structure of microtubules upon Taxol binding. In the current study we apply this technique to determine the binding mode and the conformational effects on chicken erythrocyte tubulin (CET) of another MSA, discodermolide, whose synthetic analogues may have potential use in the clinic. We confirmed that like Taxol, discodermolide binds to the taxane binding pocket in β-tubulin. However, as opposed to Taxol, which has major interactions with the M-loop, discodermolide orients itself away from this loop and towards the N-terminal H1–S2 loop. Additionally, discodermolide stabilizes microtubules mainly via its effects on interdimer contacts, specifically on the α-tubulin side, and to a lesser extent on interprotofilament contacts between adjacent β-tubulin subunits. Also, our results indicate complementary stabilizing effects of Taxol and discodermolide on the microtubules, which may explain the synergy observed between the two drugs in vivo.
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影响因子：
3.3
作者：
HYMAN, AA;SALSER, S;MITCHISON, TJ
通讯作者：
MITCHISON, TJ
影响因子：
11.5
作者：
Huang, GS;Lopez-Barcons, L;McDaid, HM
通讯作者：
McDaid, HM
影响因子：
11.2
作者：
Honore, S;Kamath, K;Jordan, MA
通讯作者：
Jordan, MA
影响因子：
2.9
作者：
DIAZ, JF;ANDREU, JM
通讯作者：
ANDREU, JM
DOI：
10.1073/pnas.0403459101
发表时间：
2004-07-06
影响因子：
11.1
作者：
Ganesh, T;Guza, RC;Kingston, DGI
通讯作者：
Kingston, DGI