View source for 8dnz


==Cryo-EM structure of the human Sec61 complex inhibited by apratoxin F==
<StructureSection load='8dnz' size='340' side='right'caption='[[8dnz]], [[Resolution|resolution]] 2.57&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8dnz]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Moorena_bouillonii Moorena bouillonii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DNZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DNZ 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]] 2.57&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0A1:O-METHYL-L-TYROSINE'>0A1</scene>, <scene name='pdbligand=IML:N-METHYL-ISOLEUCINE'>IML</scene>, <scene name='pdbligand=MAA:N-METHYL-L-ALANINE'>MAA</scene>, <scene name='pdbligand=T69:(2E)-3-{(2R,4S)-2-[(2S,3S,5S,7S)-3,7-dihydroxy-5,8,8-trimethylnonan-2-yl]-1,3-thiazolidin-4-yl}-2-methylprop-2-enoic+acid'>T69</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=8dnz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dnz OCA], [https://pdbe.org/8dnz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dnz RCSB], [https://www.ebi.ac.uk/pdbsum/8dnz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dnz ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/SC61B_HUMAN SC61B_HUMAN] Loss-of-function SEC61B variations may cause autosomal dominant polycystic liver disease (PCLD) in patients that lack variations in known causative genes, such as PRKCSH and SEC63.<ref>PMID:28375157</ref> 
== Function ==
[https://www.uniprot.org/uniprot/SC61B_HUMAN SC61B_HUMAN] Component of SEC61 channel-forming translocon complex that mediates transport of signal peptide-containing precursor polypeptides across the endoplasmic reticulum (ER) (PubMed:12475939). Forms a ribosome receptor and a gated pore in the ER membrane, both functions required for cotranslational translocation of nascent polypeptides (PubMed:12475939). The SEC61 channel is also involved in ER membrane insertion of transmembrane proteins: it mediates membrane insertion of the first few transmembrane segments of proteins, while insertion of subsequent transmembrane regions of multi-pass membrane proteins is mediated by the multi-pass translocon (MPT) complex (PubMed:32820719, PubMed:36261522). The SEC61 channel cooperates with the translocating protein TRAM1 to import nascent proteins into the ER (PubMed:19121997).<ref>PMID:12475939</ref> <ref>PMID:19121997</ref> <ref>PMID:32820719</ref> <ref>PMID:36261522</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The Sec61 complex forms a protein-conducting channel in the endoplasmic reticulum membrane that is required for secretion of soluble proteins and production of many membrane proteins. Several natural and synthetic small molecules specifically inhibit Sec61, generating cellular effects that are useful for therapeutic purposes, but their inhibitory mechanisms remain unclear. Here we present near-atomic-resolution structures of human Sec61 inhibited by a comprehensive panel of structurally distinct small molecules-cotransin, decatransin, apratoxin, ipomoeassin, mycolactone, cyclotriazadisulfonamide and eeyarestatin. All inhibitors bind to a common lipid-exposed pocket formed by the partially open lateral gate and plug domain of Sec61. Mutations conferring resistance to the inhibitors are clustered at this binding pocket. The structures indicate that Sec61 inhibitors stabilize the plug domain in a closed state, thereby preventing the protein-translocation pore from opening. Our study provides the atomic details of Sec61-inhibitor interactions and the structural framework for further pharmacological studies and drug design.

A common mechanism of Sec61 translocon inhibition by small molecules.,Itskanov S, Wang L, Junne T, Sherriff R, Xiao L, Blanchard N, Shi WQ, Forsyth C, Hoepfner D, Spiess M, Park E Nat Chem Biol. 2023 May 11. doi: 10.1038/s41589-023-01337-y. PMID:37169959<ref>PMID:37169959</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8dnz" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Moorena bouillonii]]
[[Category: Itskanov S]]
[[Category: Park E]]