Structural Insights into the Pharmacophore of Vinca Domain Inhibitors of Microtubules
Structural Insights into the Pharmacophore of Vinca Domain Inhibitors of Microtubules
复制标题
微管长春花结构域抑制剂药效团的结构见解
DOI：
10.1124/mol.115.100149
复制
发表时间：
2016-02-01
影响因子：
3.6
通讯作者：
Yang, Jinliang
中科院分区：
文献类型：
--
作者：
Wang, Yuxi;Benz, Frederick W.;Yang, Jinliang
Antibody-drug conjugates (ADCs) have achieved great success in cancer therapy in recent years. Some peptidyl microtubule inhibitors consisting of natural and unnatural amino acids, such as monomethyl auristatin E (MMAE) and F (MMAF), are extremely cytotoxic and have been used as a payload in ADCs. However, their precise molecular interaction with tubulin and microtubules remains unclear. We determined the crystal structures of tubulin in complex with three ultra-potent peptidyl microtubule inhibitors [MMAE, taltobulin (HTI- 286), and tubulysin M] at 2.5 Å. Our data showed that the three peptides bound to the vinca domain and shared a common and key pharmacophore containing two consecutive hydrophobic groups (Val, Ile-like side chain). These groups protruded in opposite directions into hydrophobic pockets on the tubulin β and α subunits. Nitrogen and oxygen atoms from the same backbone formed hydrogen bonds with Asn329 from the α subunit and Asp179 from the β subunit in a direction normal to the surface formed by the aforementioned hydrophobic groups. In addition, our crystal structure data indicated that tubulysin M bound to the β subunit alone, providing a structural explanation for its higher affinity. We also compared the conformations of two representative structurally different vinca domain compounds, ustiloxin D and vinblastine, with those of the aforementioned peptidyl ligands, and found that they shared a similar pharmacophore. Our findings lay a foundation for the rational design of novel vinca domain ligands and may facilitate the development of microtubule inhibitors with high specificity, affinity, and efficiency as payloads for ADCs in cancer therapy.
