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Human Sec61 complex bound to coibamide A
Structural highlights
FunctionSC61G_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 PubMedCoibamide 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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