R-554 / Salzman Group - LARVOL DELTA

Tumor-intrinsic PRMT5 upregulates FGL1 via methylating TCF12 to inhibit CD8+ T-cell-mediated antitumor immunity in liver cancer. (PubMed, Acta Pharm Sin B) - "Mechanistically, PRMT5 catalyzed symmetric dimethylation of transcription factor 12 (TCF12) at arginine 554 (R554), prompting the binding of TCF12 to FGL1 promoter region, which transcriptionally activated FGL1 in tumor cells. Notably, combining the PRMT5 methyltransferase inhibitor GSK591 with PD-L1 blockade efficiently inhibited liver cancer growth and improved overall survival in mice. Collectively, our findings reveal the immunosuppressive role and mechanism of PRMT5 in liver cancer and highlight that targeting PRMT5 could boost checkpoint immunotherapy efficacy."

IO biomarker • Journal • Hepatology • Liver Cancer • Oncology • Solid Tumor • CD8 • FGL1 • PRMT5 • TCF12

Preferential allosteric modulation of Otop1 channels by small molecule compounds. (PubMed, Commun Biol) - "MFaN activates Otop1 while preserving its core biophysical and pharmacological properties by associating with key residues on the channel's S5-6 and S11-12 loops, including a crucial arginine (R554) essential for Zn2+ and alkali activation. This study identifies important Otop1 modulators and structural elements underlying its gating, paving the way for further exploration of this ion channel."

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Vertebrate OTOP1 is also an alkali-activated channel. (PubMed, Nat Commun) - "Mutations of K221 and R554 at the S5-S6 and S11-S12 linkers significantly reduced alkali affinity without affecting acid activation, suggesting that different domains are responsible for acid- and alkali-activation of OTOP1...Given that the alkali-activation of OTOP1 and the required key residues were conserved in the six representative vertebrates, we cautiously propose that OTOP1 participates in alkaline sensation in vertebrates. Thus, our study identified OTOP1 as an alkali-activated channel."

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