Department of Biology and Chemistry, Laboratory of Biomolecular Research, Paul Scherrer Institut, 5232 Villigen PSI (Switzerland).
Angew Chem Int Ed Engl. 2014 Feb 3;53(6):1621-5. doi: 10.1002/anie.201307749. Epub 2014 Jan 27.
Laulimalide and peloruside A are microtubule-stabilizing agents (MSAs), the mechanism of action on microtubules of which is poorly defined. Here, using X-ray crystallography it is shown that laulimalide and peloruside A bind to a unique non-taxane site on β-tubulin and use their respective macrolide core structures to interact with a second tubulin dimer across protofilaments. At the same time, they allosterically stabilize the taxane-site M-loop that establishes lateral tubulin contacts in microtubules. Structures of ternary complexes of tubulin with laulimalide/peloruside A and epothilone A are also solved, and a crosstalk between the laulimalide/peloruside and taxane sites via the M-loop of β-tubulin is found. Together, the data define the mechanism of action of laulimalide and peloruside A on tubulin and microtubules. The data further provide a structural framework for understanding the synergy observed between two classes of MSAs in tubulin assembly and the inhibition of cancer cell growth.
laulimalide 和 peloruside A 是微管稳定剂 (MSAs)，其作用机制在微管上尚未明确。本研究通过 X 射线晶体学表明，laulimalide 和 peloruside A 结合于 β-微管蛋白上的一个独特的非紫杉烷结合位点，并利用各自的大环核心结构与沿原纤维的另一个微管二聚体相互作用。同时，它们变构稳定了 taxane 结合位点的 M 环，该环在微管中建立了横向微管接触。还解析了微管蛋白与 laulimalide/peloruside A 和 epothilone A 的三元复合物结构，发现 laulimalide/peloruside 和 taxane 结合位点通过 β-微管蛋白的 M 环存在串扰。总之，这些数据定义了 laulimalide 和 peloruside A 对微管蛋白和微管的作用机制。这些数据还为理解两类 MSAs 在微管组装和抑制癌细胞生长中观察到的协同作用提供了结构框架。
