8ouo: Difference between revisions
From Proteopedia
Jump to navigationJump to search
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Human TPC2 in Complex with Antagonist (S)-SG-094== | |||
<StructureSection load='8ouo' size='340' side='right'caption='[[8ouo]], [[Resolution|resolution]] 3.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8ouo]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8OUO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8OUO FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PCF:1,2-DIACYL-SN-GLYCERO-3-PHOSHOCHOLINE'>PCF</scene>, <scene name='pdbligand=PLD:DIUNDECYL+PHOSPHATIDYL+CHOLINE'>PLD</scene>, <scene name='pdbligand=Q7G: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'>Q7G</scene>, <scene name='pdbligand=W4E:(1S)-6-methoxy-2-methyl-7-phenoxy-1-[(4-phenoxyphenyl)methyl]-3,4-dihydro-1H-isoquinoline'>W4E</scene>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8ouo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ouo OCA], [https://pdbe.org/8ouo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ouo RCSB], [https://www.ebi.ac.uk/pdbsum/8ouo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ouo ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== 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<ref>PMID:38815576</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 8ouo" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Bohstedt T]] | |||
[[Category: Chi G]] | |||
[[Category: Duerr K]] | |||
[[Category: Fernandez-Cid A]] | |||
[[Category: Li H]] | |||
[[Category: Maclean EM]] | |||
[[Category: McKinley G]] | |||
[[Category: Mukhopadhyay SMM]] | |||
[[Category: Pike ACW]] | |||
[[Category: Wang D]] | |||
Latest revision as of 05:01, 12 June 2024
Human TPC2 in Complex with Antagonist (S)-SG-094
| ||||||||||||
