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Publication Abstract from PubMed

Two pore channels are lysosomal cation channels with crucial roles in tumor angiogenesis and viral release from endosomes. Inhibition of the two-pore channel 2 (TPC2) has emerged as potential therapeutic strategy for the treatment of cancers and viral infections, including Ebola and COVID-19. Here, we demonstrate that antagonist SG-094, a synthetic analog of the Chinese alkaloid medicine tetrandrine with increased potency and reduced toxicity, induces asymmetrical structural changes leading to a single binding pocket at only one intersubunit interface within the asymmetrical dimer. Supported by functional characterization of mutants by Ca(2+) imaging and patch clamp experiments, we identify key residues in S1 and S4 involved in compound binding to the voltage sensing domain II. SG-094 arrests IIS4 in a downward shifted state which prevents pore opening via the IIS4/S5 linker, hence resembling gating modifiers of canonical VGICs. These findings may guide the rational development of new therapeutics antagonizing TPC2 activity.

Structural basis for inhibition of the lysosomal two-pore channel TPC2 by a small molecule antagonist.,Chi G, Jaslan D, Kudrina V, Bock J, Li H, Pike ACW, Rautenberg S, Krogsaeter E, Bohstedt T, Wang D, McKinley G, Fernandez-Cid A, Mukhopadhyay SMM, Burgess-Brown NA, Keller M, Bracher F, Grimm C, Durr KL Structure. 2024 May 23:S0969-2126(24)00182-5. doi: 10.1016/j.str.2024.05.005. PMID:38815576^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.