8R67

tubulin-cryptophycin complex

8R67 の概要

• エントリーDOI: 10.2210/pdb8r67/pdb
• 分子名称: Detyrosinated tubulin alpha-1B chain, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, GLYCEROL, ... (14 entities in total)
• 機能のキーワード: cell cycle, tubulin fold, cytoskeleton, microtubule
• 由来する生物種: Rattus norvegicus (Norway rat); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 266326.15

構造登録者

Abel, A.C.,Muehlethaler, T.,Dessin, C.,Steinmetz, M.O.,Sewald, N.,Prota, A.E. (登録日: 2023-11-21, 公開日: 2024-05-22, 最終更新日: 2024-06-12)

主引用文献

Abel, A.C.,Muhlethaler, T.,Dessin, C.,Schachtsiek, T.,Sammet, B.,Sharpe, T.,Steinmetz, M.O.,Sewald, N.,Prota, A.E.
Bridging the maytansine and vinca sites: Cryptophycins target beta-tubulin's T5-loop.
J.Biol.Chem., 300:107363-107363, 2024

PubMed Abstract: Cryptophycins are microtubule-targeting agents (MTAs) that belong to the most potent antimitotic compounds known to date; however, their exact molecular mechanism of action remains unclear. Here, we present the 2.2 Å resolution X-ray crystal structure of a potent cryptophycin derivative bound to the αβ-tubulin heterodimer. The structure addresses conformational issues present in a previous 3.3 Å resolution cryo-electron microscopy structure of cryptophycin-52 bound to the maytansine site of β-tubulin. It further provides atomic details on interactions of cryptophycins, which had not been described previously, including ones that are in line with structure-activity relationship studies. Interestingly, we discovered a second cryptophycin-binding site that involves the T5-loop of β-tubulin, a critical secondary structure element involved in the exchange of the guanosine nucleotide and in the formation of longitudinal tubulin contacts in microtubules. Cryptophycins are the first natural ligands found to bind to this new "βT5-loop site" that bridges the maytansine and vinca sites. Our results offer unique avenues to rationally design novel MTAs with the capacity to modulate T5-loop dynamics and to simultaneously engage multiple β-tubulin binding sites.

PubMed: 38735475
DOI: 10.1016/j.jbc.2024.107363

実験手法

X-RAY DIFFRACTION (2.2 Å)