Structural basis of microtubule stabilization by discodermolide

5 p.-4 fig.-1 schem.
Microtubule-stabilizing agents (MSAs) are widely used in chemotherapy. Here, using X-ray crystallography we describe the detailed binding modes of two potent MSAs, (+)-discodermolide (DDM) and the DDM-paclitaxel-hybrid KS-1-199-32, in the taxane pocket of B-tubulin. Both compounds bind in a very similar hairpin conformation as previously observed in solution. However, they differentially stabilize the M-loop of B-tubulin: 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 B-tubulin helices H6 and H7 and loop S9-S10 with the M-loop, which is similar to the structural effects elicited by epothilone A, but distinct from paclitaxel. Together, our data rationalize a differential binding mechanism of DDM and KS-1-199-32 on tubulin.
This work was supported by grants from the Ministerio de Economia y Competitividad (BFU2016‐75319‐R (AEI/FEDER, UE), to J.F.D), the National Cancer Institute Grant CA077263 (A.B.S, H.M.D. and S.B.H), the Breast Cancer Research Foundation (H.M.D. and S.B.H.) and the Swiss National Science Foundation (31003A_166608; to M.O.S.). The authors acknowledge networking contribution by the COST Action CM1407 “Challenging organic syntheses inspired by nature - from natural products chemistry to drug discovery” and the COST action CM1470.