9FYD

tubulin - cryptophycin-uD[Dab] complex

これはPDB形式変換不可エントリーです。

9FYD の概要

• エントリーDOI: 10.2210/pdb9fyd/pdb
• 分子名称: Tubulin alpha-1B chain, cryptophycin-uD[Dab], PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 entities in total)
• 機能のキーワード: cell cycle, cytoskeleton, microtubule, tubulin, cryptophycin, microtubule targting agent
• 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: 265856.73

構造登録者

Dessin, C.,Schachtsiek, T.,Voss, J.,Abel, A.-C.,Neumann, B.,Stammler, H.-G.,Prota, A.E.,Sewald, N. (登録日: 2024-07-03, 公開日: 2024-10-09, 最終更新日: 2024-12-11)

主引用文献

Dessin, C.,Schachtsiek, T.,Voss, J.,Abel, A.C.,Neumann, B.,Stammler, H.G.,Prota, A.E.,Sewald, N.
Highly Cytotoxic Cryptophycin Derivatives with Modification in Unit D for Conjugation.
Angew.Chem.Int.Ed.Engl., 63:e202416210-e202416210, 2024

PubMed Abstract: Cytotoxic payloads for drug conjugates suitable for directed tumor therapy need to be highly potent and require a functional group for conjugation with the homing device (antibody, peptide, or small molecule). Cryptophycins are cyclodepsipeptides that stand out from the realm of natural products due to their extraordinarily high cytotoxicity. However, the installation of a suitable conjugation handle without compromising the toxicity is highly challenging. The unit D, natively 2-hydroxyisocaproic acid (leucic acid), was envisaged as a promising attachment site based on structural information from X-ray analysis. A versatile, scalable and efficient synthetic route towards conjugable cryptophycins with modification in unit D was developed and an array of new cryptophycin analogues was synthesized. Several derivatives, especially those containing lipophilic groups with low steric demand such as alkylated amino groups, exhibit low picomolar cytotoxicity often combined with efficacy against multidrug-resistant tumor cells. The newly established cryptophycin analogues comprise a broad range of relevant functional groups used as conjugation handles, among them amino, hydroxy, carboxy, as well as sulfur-containing derivatives. X-ray crystallographic analysis of a tubulin-bound cryptophycin together with quantitative structure activity relationship manifested rationales for the synthesis of most potent cryptophycin derivatives and further confirmed the suitability of modifications in unit D.

PubMed: 39324938
DOI: 10.1002/anie.202416210

実験手法

X-RAY DIFFRACTION (2.3 Å)