9BQ6

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

Summary for 9BQ6

• Entry DOI: 10.2210/pdb9bq6/pdb
• Descriptor: DNA topoisomerase 2-alpha, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: topoisomerase, atpase, hydrolase, isomerase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 92029.42

Authors

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

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.9 Å)