Prota Andrea E, Bargsten Katja, Redondo-Horcajo Mariano, Smith Amos B, Yang Chia-Ping H, McDaid Hayley M, Paterson Ian, Horwitz Susan B, Fernando Díaz José, Steinmetz Michel O
Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, OFLC/111, 5232, Villigen PSI, Switzerland.
Current address: Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, 8057, Zürich, Switzerland.
Chembiochem. 2017 May 18;18(10):905-909. doi: 10.1002/cbic.201600696. Epub 2017 Mar 27.
Microtubule-stabilizing agents (MSAs) are widely used in chemotherapy. Using X-ray crystallography we elucidated the detailed binding modes of two potent MSAs, (+)-discodermolide (DDM) and the DDM-paclitaxel hybrid KS-1-199-32, in the taxane pocket of β-tubulin. The two compounds bind in a very similar hairpin conformation, as previously observed in solution. However, they stabilize the M-loop of β-tubulin differently: KS-1-199-32 induces an M-loop helical conformation that is not observed for DDM. In the context of the microtubule structure, both MSAs connect the β-tubulin helices H6 and H7 and loop S9-S10 with the M-loop. This is similar to the structural effects elicited by epothilone A, but distinct from paclitaxel. Together, our data reveal differential binding mechanisms of DDM and KS-1-199-32 on tubulin.
微管稳定剂（MSAs）在化疗中被广泛应用。通过X射线晶体学，我们阐明了两种强效微管稳定剂，（+）-盘状二萜内酯（DDM）和DDM-紫杉醇杂合物KS-1-199-32，在β-微管蛋白紫杉烷口袋中的详细结合模式。这两种化合物以非常相似的发夹构象结合，正如之前在溶液中观察到的那样。然而，它们对β-微管蛋白M环的稳定作用不同：KS-1-199-32诱导出一种DDM未观察到的M环螺旋构象。在微管结构的背景下，两种微管稳定剂都将β-微管蛋白螺旋H6和H7以及环S9-S10与M环连接起来。这与埃坡霉素A引发的结构效应相似，但与紫杉醇不同。总之，我们的数据揭示了DDM和KS-1-199-32在微管蛋白上的不同结合机制。
