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Iskalni niz: "avtor" (Barbara Herlah) .

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1.
Asymmetric T-segment binding and gate dynamics govern the final stages of the type IIA topoisomerase catalytic cycle
Kristina Stevanović, Barbara Herlah, Matic Pavlin, Andrej Perdih, 2025, izvirni znanstveni članek

Povzetek: Type IIA DNA topoisomerases are molecular nanomachines that alter DNA topology during essential cellular processes. The final steps of their catalytic cycle, after translocation of the transported (T-) segment into the C- gate, are still not fully understood. Here, we performed all-atom molecular dynamics simulations of several conformational states of Saccharomyces cerevisiae topoisomerase IIA, each with a T-segment inserted into the C- gate. Bound ATP and ADP nucleotides allosterically modulated the N-gate dynamics, likely stabilizing the dimer and preventing premature dissociation. The T-segment was asymmetrically bound and stabilized within the C- gate by positively charged residues, and this gate remained structurally rigid, highlighting its role as a retention site. The positioning of the T-segment in the C-gate allosterically influenced the G-segment to a straighter geometry that favors religation and release. Our simulations support coordinated release of DNA segments and point to a potentially important role for dynamic communication between the gates in the mechanism. These results provide new insights into the late stages of the catalytic cycle and highlight the intertwined roles of nucleotide binding, DNA topology and coupled protein domain dynamics in regulating this important enzyme.
Ključne besede: type IIA DNA topoisomerase, T-segment, C-gate, catalytic cycle, molecular dynamics
Objavljeno v DiRROS: 19.09.2025; Ogledov: 786; Prenosov: 636
.pdf Celotno besedilo (10,82 MB)
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2.
Nature-inspired substituted 3-(imidazol-2-yl) morpholines targeting human topoisomerase IIα : dynophore-derived discovery
Barbara Herlah, Matej Janežič, Iza Ogris, Simona Golič Grdadolnik, Katja Kološa, Sonja Žabkar, Bojana Žegura, Andrej Perdih, 2024, izvirni znanstveni članek

Povzetek: The molecular nanomachine, human DNA topoisomerase IIα, plays a crucial role in replication, transcription, and recombination by catalyzing topological changes in the DNA, rendering it an optimal target for cancer chemotherapy. Current clinical topoisomerase II poisons often cause secondary tumors as side effects due to the accumulation of double-strand breaks in the DNA, spurring the development of catalytic inhibitors. Here, we used a dynamic pharmacophore approach to develop catalytic inhibitors targeting the ATP binding site of human DNA topoisomerase IIα. Our screening of a library of nature-inspired compounds led to the discovery of a class of 3-(imidazol-2-yl) morpholines as potent catalytic inhibitors that bind to the ATPase domain. Further experimental and computational studies identified hit compound 17, which exhibited selectivity against the human DNA topoisomerase IIα versus human protein kinases, cytotoxicity against several human cancer cells, and did not induce DNA double-strand breaks, making it distinct from clinical topoisomerase II poisons. This study integrates an innovative natural product-inspired chemistry and successful implementation of a molecular design strategy that incorporates a dynamic component of ligand-target molecular recognition, with comprehensive experimental characterization leading to hit compounds with potential impact on the development of more efficient chemotherapies.
Ključne besede: topoisomerase II, catalytic inhibitors, chemotherapy, DNA damage, cancer
Objavljeno v DiRROS: 03.06.2024; Ogledov: 1779; Prenosov: 1105
.pdf Celotno besedilo (7,99 MB)
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