8dnx

From Proteopedia

(Difference between revisions)

Current revision

Cryo-EM structure of the human Sec61 complex inhibited by cotransin

Structural highlights

8dnx is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.98Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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]^[1] ^[2]

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^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ McGilvray PT, Anghel SA, Sundaram A, Zhong F, Trnka MJ, Fuller JR, Hu H, Burlingame AL, Keenan RJ. An ER translocon for multi-pass membrane protein biogenesis. Elife. 2020 Aug 21;9:e56889. PMID:32820719 doi:10.7554/eLife.56889
↑ Sundaram A, Yamsek M, Zhong F, Hooda Y, Hegde RS, Keenan RJ. Substrate-driven assembly of a translocon for multipass membrane proteins. Nature. 2022 Nov;611(7934):167-172. PMID:36261522 doi:10.1038/s41586-022-05330-8
↑ Itskanov S, Wang L, Junne T, Sherriff R, Xiao L, Blanchard N, Shi WQ, Forsyth C, Hoepfner D, Spiess M, Park E. A common mechanism of Sec61 translocon inhibition by small molecules. Nat Chem Biol. 2023 May 11. PMID:37169959 doi:10.1038/s41589-023-01337-y

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8dnx"

Categories: Homo sapiens | Large Structures | Synthetic construct | Itskanov S | Park E

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[8dnx]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DNX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DNX FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MAA:N-METHYL-L-ALANINE'>MAA</scene>, <scene name='pdbligand=MLE:N-METHYLLEUCINE'>MLE</scene>, <scene name='pdbligand=SZF:1-methoxy-N-methyl-L-tryptophan'>SZF</scene>, <scene name='pdbligand=SZR:(2R)-4-cyano-2-hydroxybutanoic+acid'>SZR</scene>, <scene name='pdbligand=T09:(2S,4R)-2-amino-4-methyloctanoic+acid'>T09</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.98&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MAA:N-METHYL-L-ALANINE'>MAA</scene>, <scene name='pdbligand=MLE:N-METHYLLEUCINE'>MLE</scene>, <scene name='pdbligand=SZF:1-methoxy-N-methyl-L-tryptophan'>SZF</scene>, <scene name='pdbligand=SZR:(2R)-4-cyano-2-hydroxybutanoic+acid'>SZR</scene>, <scene name='pdbligand=T09:(2S,4R)-2-amino-4-methyloctanoic+acid'>T09</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=8dnx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dnx OCA], [https://pdbe.org/8dnx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dnx RCSB], [https://www.ebi.ac.uk/pdbsum/8dnx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dnx ProSAT]</span></td></tr>
 </table>

8dnx

From Proteopedia

Current revision

Cryo-EM structure of the human Sec61 complex inhibited by cotransin

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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