9MP1

Crystal structure of mithramycin analogue MTM SA-7-methyl-Trp in complex with double-stranded DNA AGAGGCCTCT

これはPDB形式変換不可エントリーです。

9MP1 の概要

• エントリーDOI: 10.2210/pdb9mp1/pdb
• 関連するPDBエントリー: 9MOZ
• 分子名称: DNA (5'-D(*AP*GP*AP*GP*GP*CP*CP*TP*CP*T)-3'), methyl (2S)-2-({(2S)-2-[(2R,3S)-3-{[(2S,4R,5R,6R)-4-{[(2S,4R,5S,6R)-4-{[(2S,4S,5R,6R)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy}-5-hydroxy-6-methyloxan-2-yl]oxy}-5-hydroxy-6-methyloxan-2-yl]oxy}-7-{[(2S,4R,5R,6R)-4-{[(2S,4R,5S,6R)-4,5-dihydroxy-6-methyloxan-2-yl]oxy}-5-hydroxy-6-methyloxan-2-yl]oxy}-5,10-dihydroxy-6-methyl-4-oxo-1,2,3,4-tetrahydroanthracen-2-yl]-2-methoxyacetyl}amino)-3-(7-methyl-1H-indol-3-yl)propanoate (non-preferred name), ZINC ION, ... (5 entities in total)
• 機能のキーワード: dna-drug complex, transcription, minor groove, natural product, dna
• 由来する生物種: synthetic construct
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 9099.50

構造登録者

Hou, C.,Tsodikov, O.V. (登録日: 2024-12-29, 公開日: 2025-04-30, 最終更新日: 2025-06-11)

主引用文献

Hou, C.,Bhosale, S.,Yasuda, K.,Yetirajam, R.,Leggas, M.,Rohr, J.,Tsodikov, O.V.
The Position of Indole Methylation Controls the Structure, DNA Binding, and Cellular Functions of Mithramycin SA-Trp Analogues.
Chembiochem, 26:e202401084-e202401084, 2025

PubMed Abstract: Mithramycin (MTM) is a polyketide anti-cancer natural product, which functions by noncovalent binding to DNA in the minor groove without intercalation, resulting in inhibiting transcription at G/C-rich promoters. MTM is a potent inhibitor of cancer cells, such as Ewing sarcoma, driven by abnormal fusions involving ETS family transcription factors FLI1 and ERG. However, MTM is rather toxic and non-selective; therefore, safer, selective analogues of MTM are required for use in clinic as anti-cancer drugs. In this study by using a combination of X-ray crystallographic, biophysical, cell and molecular biological techniques, we explored structural and functional consequences of 3-side chain methylation at positions 5, 6 and 7 of the indole ring of the potent analogue MTM SA-Trp. We showed that the conformation of the analogues in complexes with DNA, their DNA binding function, cytotoxicity, selectivity and potency as transcription antagonists depended on the position of the methylation. MTM SA-5-methyl-Trp emerged as the most selective analogue, presumably due to the right balance of the DNA binding and the solvent exposure of the 3-side chain. This study demonstrates that minor chemical changes can have strong effects in analogue development and paves a way to further development of next generation MTM analogues.

PubMed: 40246689
DOI: 10.1002/cbic.202401084

実験手法

X-RAY DIFFRACTION (2.08 Å)