View source for 8dnw


==Cryo-EM structure of the human Sec61 complex in a partially-open apo state (Class 2)==
<StructureSection load='8dnw' size='340' side='right'caption='[[8dnw]], [[Resolution|resolution]] 3.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8dnw]] is a 3 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=8DNW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DNW 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]] 3.4&#8491;</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=8dnw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dnw OCA], [https://pdbe.org/8dnw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dnw RCSB], [https://www.ebi.ac.uk/pdbsum/8dnw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dnw ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/SC61G_HUMAN SC61G_HUMAN] Component of SEC61 channel-forming translocon complex that mediates transport of signal peptide-containing precursor polypeptides across the endoplasmic reticulum (ER) (By similarity). Forms a ribosome receptor and a gated pore in the ER membrane, both functions required for cotranslational translocation of nascent polypeptides (By similarity). 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 (By similarity).[UniProtKB:P60058][UniProtKB:P61619]<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 8dnw" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Itskanov S]]
[[Category: Park E]]