5BMV

CRYSTAL STRUCTURE OF TUBULIN-STATHMIN-TTL-Vinblastine COMPLEX

5BMV の概要

• エントリーDOI: 10.2210/pdb5bmv/pdb
• 分子名称: Tubulin alpha-1B chain, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, (2ALPHA,2'BETA,3BETA,4ALPHA,5BETA)-VINCALEUKOBLASTINE, ... (13 entities in total)
• 機能のキーワード: complex, structural protein
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• 細胞内の位置: Cytoplasm, cytoskeleton: P81947 P02554; Golgi apparatus : P63043
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 265948.62

構造登録者

Wang, Y.,Chen, Q.,Zhang, R. (登録日: 2015-05-23, 公開日: 2016-07-13, 最終更新日: 2023-11-08)

主引用文献

Wang, Y.,Benz, F.W.,Wu, Y.,Wang, Q.,Chen, Y.,Chen, X.,Li, H.,Zhang, Y.,Zhang, R.,Yang, J.
Structural Insights into the Pharmacophore of Vinca Domain Inhibitors of Microtubules.
Mol.Pharmacol., 89:233-242, 2016

PubMed Abstract: 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.

PubMed: 26660762
DOI: 10.1124/mol.115.100149

実験手法

X-RAY DIFFRACTION (2.5 Å)