6CLW

Crystal structure of TnmH

Summary for 6CLW

• Entry DOI: 10.2210/pdb6clw/pdb
• Descriptor: O-methyltransferase (2 entities in total)
• Functional Keywords: methyltransferase, biosynthetic protein
• Biological source: Streptomyces sp. CB03234
• Total number of polymer chains: 2
• Total formula weight: 77133.75

Authors

Chang, C.Y.,Annaval, T.,Adhikari, A.,Yan, X.,Shen, B. (deposition date: 2018-03-02, release date: 2019-03-06, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.74 Å)