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Methicillin-resistant Staphylococcus aureus (MRSA) infection has rapidly spread through various routes. A genomic analysis of clinical MRSA samples revealed an unknown protein, Sav2152, predicted to be a haloacid dehalogenase (HAD)-like hydrolase, making it a potential candidate for a novel drug target. In this study, we determined the crystal structure of Sav2152, which consists of a C2-type cap domain and a core domain. The core domain contains four motifs involved in phosphatase activity that depend on the presence of Mg2+ ions. Specifically, residues D10, D12, and D233, which closely correspond to key residues in structurally homolog proteins, are responsible for binding to the metal ion and are known to play critical roles in phosphatase activity. Our findings indicate that the Mg2+ ion known to stabilize local regions surrounding it, however, paradoxically, destabilizes the local region. Through mutant screening, we identified D10 and D12 as crucial residues for metal binding and maintaining structural stability via various uncharacterized intra-protein interactions, respectively. Substituting D10 with Ala effectively prevents the interaction with Mg2+ ions. The mutation of D12 disrupts important structural associations mediated by D12, leading to a decrease in the stability of Sav2152 and an enhancement in binding affinity to Mg2+ ions. Additionally, our study revealed that D237 can replace D12 and retain phosphatase activity. In summary, our work uncovers the novel role of metal ions in HAD-like phosphatase activity. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to determine the efficacy and safety of perampanel added to monotherapy in patients with focal‐onset seizures, with or without secondarily generalized tonic‐clonic seizures. Materials & Methods: In this multicentre, open‐label trial, enrolled patients were treated with perampanel monotherapy. During a 12‐week titration period, perampanel was incrementally increased by 2 mg/d over ≥2‐week intervals. Patients then entered a 24‐week maintenance period. The primary objective was to investigate the 50% responder rate in total seizure frequency, with 75% and 100% responder rates as secondary objectives. Treatment‐emergent adverse events (TEAEs) and adverse drug reactions were recorded. A post hoc analysis was performed to investigate the effect of titration speed and different concomitant AEDs on the efficacy and safety of perampanel. Results: Of the 85 patients analysed, seizure reductions of 50%, 75% and 100% were observed in 80.0% (95% confidence interval [CI]: 69.9‐87.9), 71.8% (95% CI: 61.0‐81.0) and 47.1% (95% CI: 36.1‐58.2) during the maintenance period, respectively. The 50%, 75% and 100% response rates in patients with secondarily generalized tonic‐clonic seizures were 87.5% (95% CI: 61.7‐98.5), 87.5% (95% CI: 61.7‐98.5) and 75.0% (95% CI: 47.6‐92.7), respectively. The most common TEAEs were dizziness (50.0%), somnolence (9.8%) and headache (8.8%). The efficacy outcomes and safety profile of perampanel were more favourable with slow titration and relatively consistent when stratified by concomitant AEDs. Conclusions: Perampanel was effective and well tolerated as a first add‐on to monotherapy in patients with focal‐onset seizures, with or without secondarily generalized seizures. [ABSTRACT FROM AUTHOR]