Structural Insights into the Pharmacophore of Vinca Domain Inhibitors of Microtubules

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	Structural Insights into the Pharmacophore of Vinca Domain Inhibitors of Microtubules
	Wang, YX; Benz, FW; Wu, YP; Wang, QS; Chen, YF; Chen, XZ; Li, HY; Zhang, YH; Zhang, RD; Yang, JL
刊名	MOLECULAR PHARMACOLOGY
	2016
卷号	89 期号:2 页码:233—242
关键词	TUBULIN CHEMOTHERAPY COLCHICINE AGENTS LIGANDS
ISSN号	0026-895X
通讯作者	Zhang, RD ; Yang, JL (reprint author), Sichuan Univ, West China Hosp, State Key Lab Biotherapy, 3-17 Renmin South Rd, Chengdu 610041, Peoples R China. ; Zhang, RD ; Yang, JL (reprint author), Sichuan Univ, West China Hosp, Ctr Canc, 3-17 Renmin South Rd, Chengdu 610041, Peoples R China. ; Zhang, RD ; Yang, JL (reprint author), Collaborat Innovat Ctr Biotherapy, 3-17 Renmin South Rd, Chengdu 610041, Peoples R China.
英文摘要	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 angstrom. 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 beta and alpha subunits. Nitrogen and oxygen atoms from the same backbone formed hydrogen bonds with Asn329 from the a subunit and Asp179 from the beta 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 beta 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.
收录类别	SCI
语种	英语
WOS记录号	WOS:000369305700003
内容类型	期刊论文
源URL	[http://ir.sinap.ac.cn/handle/331007/25843]
专题	上海应用物理研究所_中科院上海应用物理研究所2011-2017年
推荐引用方式 GB/T 7714	Wang, YX,Benz, FW,Wu, YP,et al. Structural Insights into the Pharmacophore of Vinca Domain Inhibitors of Microtubules[J]. MOLECULAR PHARMACOLOGY,2016,89(2):233—242.
APA	Wang, YX.,Benz, FW.,Wu, YP.,Wang, QS.,Chen, YF.,...&Yang, JL.(2016).Structural Insights into the Pharmacophore of Vinca Domain Inhibitors of Microtubules.MOLECULAR PHARMACOLOGY,89(2),233—242.
MLA	Wang, YX,et al."Structural Insights into the Pharmacophore of Vinca Domain Inhibitors of Microtubules".MOLECULAR PHARMACOLOGY 89.2(2016):233—242.