9BQ7

Human Topoisomerase 2 Alpha ATPase domain bound to BNS22 and non-hydrolyzable ATP analog AMPPNP

これはPDB形式変換不可エントリーです。

9BQ7 の概要

• エントリーDOI: 10.2210/pdb9bq7/pdb
• 関連するPDBエントリー: 9bq6
• 分子名称: DNA topoisomerase 2-alpha, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, MAGNESIUM ION, ... (7 entities in total)
• 機能のキーワード: topoisomerase, atpase, hydrolase, isomerase-inhibitor complex, isomerase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 93007.34

構造登録者

Cong, A.T.Q.,Austin, C.A.,Kubes, J.,Karabanovich, G.,Melnikova, I.,Lencova, O.,Kollarova, P.,Piskackova, H.B.,Kerestes, V.,Applova, L.,Arrouye, L.,Alvey, J.A.,Paluncic, J.,Witter, T.L.,Jirkovska, A.,Kunes, J.,Sterbova, P.,Sterba, M.,Simunek, T.,Roh, J.,Schellenberg, M.J. (登録日: 2024-05-09, 公開日: 2025-06-25)

主引用文献

Kubes, J.,Karabanovich, G.,Cong, A.T.Q.,Melnikova, I.,Lencova, O.,Kollarova, P.,Bavlovic Piskackova, H.,Kerestes, V.,Applova, L.,Arrouye, L.C.M.,Alvey, J.R.,Paluncic, J.,Witter, T.L.,Jirkovska, A.,Kunes, J.,Sterbova-Kovarikova, P.,Austin, C.A.,Sterba, M.,Simunek, T.,Roh, J.,Schellenberg, M.J.
Topobexin targets the Topoisomerase II ATPase domain for beta isoform-selective inhibition and anthracycline cardioprotection.
Nat Commun, 16:4928-4928, 2025

PubMed Abstract: Topoisomerase II alpha and beta (TOP2A and TOP2B) isoenzymes perform essential and non-redundant cellular functions. Anthracyclines induce their potent anti-cancer effects primarily via TOP2A, but at the same time they induce a dose limiting cardiotoxicity through TOP2B. Here we describe the development of the obex class of TOP2 inhibitors that bind to a previously unidentified druggable pocket in the TOP2 ATPase domain to act as allosteric catalytic inhibitors by locking the ATPase domain conformation with the capability of isoform-selective inhibition. Through rational drug design we have developed topobexin, which interacts with residues that differ between TOP2A and TOP2B to provide inhibition that is both selective for TOP2B and superior to dexrazoxane. Topobexin is a potent protectant against chronic anthracycline cardiotoxicity in an animal model. This demonstration of TOP2 isoform-specific inhibition underscores the broader potential to improve drug specificity and minimize adverse effects in various medical treatments.

PubMed: 40425539
DOI: 10.1038/s41467-025-60167-9

実験手法

X-RAY DIFFRACTION (2.05 Å)