8OUO
Human TPC2 in Complex with Antagonist (S)-SG-094
Summary for 8OUO
| Entry DOI | 10.2210/pdb8ouo/pdb |
| EMDB information | 17197 |
| Descriptor | Two pore channel protein 2, di-heneicosanoyl phosphatidyl choline, 2-{[(4-O-alpha-D-glucopyranosyl-alpha-D-glucopyranosyl)oxy]methyl}-4-{[(3beta,9beta,14beta,17beta,25R)-spirost-5-en-3-yl]oxy}butyl 4-O-alpha-D-glucopyranosyl-alpha-D-glucopyranoside, ... (6 entities in total) |
| Functional Keywords | tpc2, two-pore channel, ion channel, inhibitor, homodimer, metal transport |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 180657.42 |
| Authors | Chi, G.,Pike, A.C.W.,Maclean, E.M.,Li, H.,Mukhopadhyay, S.M.M.,Bohstedt, T.,Wang, D.,McKinley, G.,Fernandez-Cid, A.,Duerr, K. (deposition date: 2023-04-24, release date: 2024-06-12, Last modification date: 2024-10-23) |
| Primary citation | Chi, G.,Jaslan, D.,Kudrina, V.,Bock, J.,Li, H.,Pike, A.C.W.,Rautenberg, S.,Krogsaeter, E.,Bohstedt, T.,Wang, D.,McKinley, G.,Fernandez-Cid, A.,Mukhopadhyay, S.M.M.,Burgess-Brown, N.A.,Keller, M.,Bracher, F.,Grimm, C.,Durr, K.L. Structural basis for inhibition of the lysosomal two-pore channel TPC2 by a small molecule antagonist. Structure, 32:1137-1149.e4, 2024 Cited by PubMed Abstract: 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 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. PubMed: 38815576DOI: 10.1016/j.str.2024.05.005 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3 Å) |
Structure validation
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