6CLX
Crystal structure of TnmH in complex with SAM
Summary for 6CLX
| Entry DOI | 10.2210/pdb6clx/pdb |
| Descriptor | O-methyltransferase, S-ADENOSYLMETHIONINE (3 entities in total) |
| Functional Keywords | methyltransferase, biosynthetic protein |
| Biological source | Streptomyces sp. CB03234 |
| Total number of polymer chains | 2 |
| Total formula weight | 78774.73 |
| 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: 2024-10-16) |
| 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 Cited by 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: 32658465DOI: 10.1021/acs.jmedchem.0c00799 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.73 Å) |
Structure validation
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