CAS OpenIR  > 中科院上海应用物理研究所2011-2018年
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; Yang, JL (reprint author), Sichuan Univ, West China Hosp, State Key Lab Biotherapy, 3-17 Renmin South Rd, Chengdu 610041, Peoples R China.; Yang, JL (reprint author), Sichuan Univ, West China Hosp, Ctr Canc, 3-17 Renmin South Rd, Chengdu 610041, Peoples R China.; Yang, JL (reprint author), Collaborat Innovat Ctr Biotherapy, 3-17 Renmin South Rd, Chengdu 610041, Peoples R China.
2016
Source PublicationMOLECULAR PHARMACOLOGY
ISSN0026-895X
Volume89Issue:2Pages:233—242
Subtype期刊文献
AbstractAntibody-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.
KeywordTubulin Chemotherapy Colchicine Agents Ligands
DOI10.1124/mol.115.100149
Indexed BySCI
Language英语
WOS IDWOS:000369305700003
Citation statistics
Document Type期刊论文
Identifierhttp://ir.sinap.ac.cn/handle/331007/25843
Collection中科院上海应用物理研究所2011-2018年
Corresponding AuthorZhang, RD; Yang, JL (reprint author), Sichuan Univ, West China Hosp, State Key Lab Biotherapy, 3-17 Renmin South Rd, Chengdu 610041, Peoples R China.; Yang, JL (reprint author), Sichuan Univ, West China Hosp, Ctr Canc, 3-17 Renmin South Rd, Chengdu 610041, Peoples R China.; Yang, JL (reprint author), Collaborat Innovat Ctr Biotherapy, 3-17 Renmin South Rd, Chengdu 610041, Peoples R China.
Recommended Citation
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.
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