Work

Networked salt-bridges mediate magnesium-dependent conformational dynamics and functional regulation in type IA topoisomerases

Year: 2026

Type: article

Abstract: Protein conformational dynamics are fundamental to enzyme function, yet the molecular mechanisms by which these dynamics are regulated remain poorly understood. Here, we reveal that a conserved network of salt-bridges, modulated by magnesium ions, serves as a key regulator of conformational transitions in Type IA topoisomerases (TopIA). Using a combination of single-molecule and ensemble measurements, molecular dynamics simulations, and targeted protein mutagenesis, we demonstrate that Mg²⁺ binding to a distinct divalent metal binding site orchestrates the opening and closing of the protein-mediated DNA gate-a critical step in TopIA's catalytic cycle. Our results show that magnesium tunes the kinetics of the salt-bridge network's configurational switching, directly impacting enzyme activity and providing a safeguard against DNA damage under Mg²⁺ depletion. This work provides a chemical and structural framework for understanding divalent cation-dependent regulation of protein function via networked salt-bridges. Our findings open additional avenues for the rational design of cation-sensitive proteins and inhibitors, and highlight an evolutionarily conserved strategy for coupling environmental sensing to molecular function.

Source: Nature Communications

DOI: 10.1038/s41467-026-72556-9

Authors: Yeonee Seol, Yuk-Ching Tse-Dinh, Keir C. Neuman

Institutions: National Institutes of Health, National Heart, Lung, and Blood Institute, Florida International University

Language: English

Topic: Protein Structure and Dynamics

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $6,990

Funders: National Institutes of Health, National Heart, Lung, and Blood Institute