7dxf
From Proteopedia
(Difference between revisions)
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==Structure of BTDM-bound human TRPC6 nanodisc at 2.9 angstrom in high calcium state== | ==Structure of BTDM-bound human TRPC6 nanodisc at 2.9 angstrom in high calcium state== | ||
| - | <StructureSection load='7dxf' size='340' side='right'caption='[[7dxf]]' scene=''> | + | <StructureSection load='7dxf' size='340' side='right'caption='[[7dxf]], [[Resolution|resolution]] 2.90Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7DXF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7DXF FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7dxf]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7DXF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7DXF FirstGlance]. <br> |
| - | </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=7dxf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7dxf OCA], [https://pdbe.org/7dxf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7dxf RCSB], [https://www.ebi.ac.uk/pdbsum/7dxf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7dxf ProSAT]</span></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=98R:[(2S)-2-[(E)-octadec-10-enoyl]oxy-3-oxidanyl-propyl]+octadec-10-enoate'>98R</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=POV:(2S)-3-(HEXADECANOYLOXY)-2-[(9Z)-OCTADEC-9-ENOYLOXY]PROPYL+2-(TRIMETHYLAMMONIO)ETHYL+PHOSPHATE'>POV</scene>, <scene name='pdbligand=W99:[2-(1,3-benzodioxol-5-ylamino)-1,3-thiazol-4-yl]-[(3R,5S)-3,5-dimethylpiperidin-1-yl]methanone'>W99</scene>, <scene name='pdbligand=Y01:CHOLESTEROL+HEMISUCCINATE'>Y01</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=7dxf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7dxf OCA], [https://pdbe.org/7dxf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7dxf RCSB], [https://www.ebi.ac.uk/pdbsum/7dxf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7dxf ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Disease == | ||
| + | [[https://www.uniprot.org/uniprot/TRPC6_HUMAN TRPC6_HUMAN]] Familial idiopathic steroid-resistant nephrotic syndrome with focal segmental hyalinosis. The disease is caused by mutations affecting the gene represented in this entry. | ||
| + | == Function == | ||
| + | [[https://www.uniprot.org/uniprot/TRPC6_HUMAN TRPC6_HUMAN]] Thought to form a receptor-activated non-selective calcium permeant cation channel (PubMed:19936226, PubMed:23291369). Probably is operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors. Activated by diacylglycerol (DAG) in a membrane-delimited fashion, independently of protein kinase C (PubMed:26892346). Seems not to be activated by intracellular calcium store depletion.<ref>PMID:19936226</ref> <ref>PMID:23291369</ref> <ref>PMID:26892346</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | TRPC3 and TRPC6 channels are calcium-permeable non-selective cation channels that are involved in many physiological processes. The gain-of-function (GOF) mutations of TRPC6 lead to familial focal segmental glomerulosclerosis (FSGS) in humans, but their pathogenic mechanism remains elusive. Here, we report the cryo-EM structures of human TRPC3 in both high-calcium and low-calcium conditions. Based on these structures and accompanying electrophysiological studies, we identified both inhibitory and activating calcium-binding sites in TRPC3 that couple intracellular calcium concentrations to the basal channel activity. These calcium sensors are also structurally and functionally conserved in TRPC6. We uncovered that the GOF mutations of TRPC6 activate the channel by allosterically abolishing the inhibitory effects of intracellular calcium. Furthermore, structures of human TRPC6 in complex with two chemically distinct inhibitors bound at different ligand-binding pockets reveal different conformations of the transmembrane domain, providing templates for further structure-based drug design targeting TRPC6-related diseases such as FSGS. | ||
| + | |||
| + | Structural mechanism of human TRPC3 and TRPC6 channel regulation by their intracellular calcium-binding sites.,Guo W, Tang Q, Wei M, Kang Y, Wu JX, Chen L Neuron. 2022 Mar 16;110(6):1023-1035.e5. doi: 10.1016/j.neuron.2021.12.023. Epub , 2022 Jan 19. PMID:35051376<ref>PMID:35051376</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7dxf" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Chen L]] | + | [[Category: Chen, L]] |
| - | [[Category: Guo W]] | + | [[Category: Guo, W]] |
| + | [[Category: Btdm]] | ||
| + | [[Category: Calcium]] | ||
| + | [[Category: Channel]] | ||
| + | [[Category: Fsg]] | ||
| + | [[Category: Membrane protein]] | ||
| + | [[Category: Trpc]] | ||
| + | [[Category: Trpc6]] | ||
Revision as of 06:30, 18 August 2022
Structure of BTDM-bound human TRPC6 nanodisc at 2.9 angstrom in high calcium state
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Categories: Large Structures | Chen, L | Guo, W | Btdm | Calcium | Channel | Fsg | Membrane protein | Trpc | Trpc6
