A labile sulfur ligand in a three-cysteine-coordinated [2Fe-2S] cluster mediates sulfide sensing in NreB.
basic_science · Level V
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- Record sourced from PubMed, PMID 42218159.
- Also identified by DOI 10.1038/s41467-026-73842-2.
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Abstract
Iron-sulfur clusters are versatile protein cofactors involved in diverse biological processes, but their role in hydrogen sulfide/hydrosulfide (H<sub>2</sub>S/HS<sup>-</sup>) sensing remains largely unexplored. Here, we report that the Bacillus licheniformis sensor kinase NreB contains an unusual [2Fe-2S] cluster within its PAS domain. A 1.52-Å crystal structure reveals a distinct coordination geometry where three conserved cysteine residues and a non-cysteinyl sulfur ligand stabilize the cluster. Biochemical and native mass spectrometry support assignment of the predominant ligand state as -SH and show enrichment of -SSH/SSOH-like state upon sulfide exposure in the presence of O<sub>2</sub>, correlating with increased NreB kinase activity. Electron paramagnetic resonance spectroscopy shows that the cluster retains its oxidized [2Fe-2S]<sup>2+</sup> state during sulfide-sensing. Molecular dynamics simulations further reveal transient solvent and HS<sup>-</sup> accessibility to the buried cluster, providing a physical basis for ligand entry. Here, we show that bacteria sense sulfide via a three-cysteine-coordinated Fe-S cluster with a labile sulfur ligand.