View source for 9yws


==Human Sec61 complex bound to coibamide A==
<StructureSection load='9yws' size='340' side='right'caption='[[9yws]], [[Resolution|resolution]] 3.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9yws]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Leptolyngbya_sp. Leptolyngbya sp.]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9YWS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9YWS 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]] 3.1&#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=33X:N-METHYL-D-ALANINE'>33X</scene>, <scene name='pdbligand=A1CZ7:(2~{S})-3-methoxy-2-(methylamino)propanoic+acid'>A1CZ7</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=IML:N-METHYL-ISOLEUCINE'>IML</scene>, <scene name='pdbligand=MLE:N-METHYLLEUCINE'>MLE</scene>, <scene name='pdbligand=NZC:N-METHYLIDENE-L-THREONINE'>NZC</scene>, <scene name='pdbligand=O7G:(2~{S})-2-(dimethylamino)-3-methyl-butanoic+acid'>O7G</scene>, <scene name='pdbligand=VAD:DEAMINOHYDROXYVALINE'>VAD</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=9yws FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9yws OCA], [https://pdbe.org/9yws PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9yws RCSB], [https://www.ebi.ac.uk/pdbsum/9yws PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9yws 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 ==
Coibamide A (CbA) is a cyclic depsipeptide that inhibits the function of the Sec61 translocon and exhibits significant antitumor activity. However, its broad Sec61 inhibition results in non-selective cytotoxicity, limiting therapeutic applications. To elucidate the molecular mechanism of CbA-mediated Sec61 blockade and enable rational prodrug design, we determined the cryo-EM structure of human Sec61 bound to CbA at 3.1 A resolution. The structure reveals that CbA adopts a distinctive lasso-like conformation and occupies the lateral gate of Sec61, a binding site shared with other Sec61 inhibitors, while forming a particularly more expansive set of interactions with the lateral gate. Guided by these structural insights, we conducted structure-activity relationship studies and developed prodrug strategies that modulate CbA's antitumor activity through the controlled perturbation of intramolecular and protein hydrogen bonding interactions. Together, these results establish a structure-guided strategy for prodrug design of CbA and demonstrate the general applicability of backbone-caging to enhance the tolerability of Sec61 inhibitors.

Structure-based design of Sec61 translocon targeting prodrugs minimize off-target toxicity.,Hao Q, Wang L, Pan H, Xiao X, Dong W, Pan W, Sun J, Su W, Fang L, Park E, Yao G Cell Chem Biol. 2026 Jun 18;33(6):823-836.e21. doi: , 10.1016/j.chembiol.2026.05.006. Epub 2026 Jun 9. PMID:42263680<ref>PMID:42263680</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9yws" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Leptolyngbya sp]]
[[Category: Park E]]
[[Category: Wang L]]