6CLX

Crystal structure of TnmH in complex with SAM

6CLX の概要

• エントリーDOI: 10.2210/pdb6clx/pdb
• 分子名称: O-methyltransferase, S-ADENOSYLMETHIONINE (3 entities in total)
• 機能のキーワード: methyltransferase, biosynthetic protein
• 由来する生物種: Streptomyces sp. CB03234
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 78774.73

構造登録者

Chang, C.Y.,Annaval, T.,Adhikari, A.,Yan, X.,Shen, B. (登録日: 2018-03-02, 公開日: 2019-03-06, 最終更新日: 2024-10-16)

主引用文献

Adhikari, A.,Teijaro, C.N.,Yan, X.,Chang, C.Y.,Gui, C.,Liu, Y.C.,Crnovcic, I.,Yang, D.,Annaval, T.,Rader, C.,Shen, B.
Characterization of TnmH as anO-Methyltransferase Revealing Insights into Tiancimycin Biosynthesis and Enabling a Biocatalytic Strategy To Prepare Antibody-Tiancimycin Conjugates.
J.Med.Chem., 63:8432-8441, 2020

PubMed Abstract: The enediynes are among the most cytotoxic molecules known, and their use as anticancer drugs has been successfully demonstrated by targeted delivery. Clinical advancement of the anthraquinone-fused enediynes has been hindered by their low titers and lack of functional groups to enable the preparation of antibody-drug conjugates (ADCs). Here we report biochemical and structural characterization of TnmH from the tiancimycin (TNM) biosynthetic pathway, revealing that (i) TnmH catalyzes regiospecific methylation at the C-7 hydroxyl group, (ii) TnmH exhibits broad substrate promiscuity toward hydroxyanthraquinones and S-alkylated SAM analogues and catalyzes efficient installation of reactive alkyl handles, (iii) the X-ray crystal structure of TnmH provides the molecular basis to account for its broad substrate promiscuity, and (iv) TnmH as a biocatalyst enables the development of novel conjugation strategies to prepare antibody-TNM conjugates. These findings should greatly facilitate the construction and evaluation of antibody-TNM conjugates as next-generation ADCs for targeted chemotherapy.

PubMed: 32658465
DOI: 10.1021/acs.jmedchem.0c00799

実験手法

X-RAY DIFFRACTION (2.73 Å)