9YWS

Human Sec61 complex bound to coibamide A

This is a non-PDB format compatible entry.

Summary for 9YWS

• Entry DOI: 10.2210/pdb9yws/pdb
• EMDB information: 73558
• Descriptor: Protein transport protein Sec61 subunit gamma, Protein transport protein Sec61 subunit beta, Protein transport protein Sec61 subunit alpha isoform 1, ... (5 entities in total)
• Functional Keywords: sec61, coibamide, endoplasmic reticulum, depsipeptide, protein transport
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 71634.51

Authors

Park, E.,Wang, L. (deposition date: 2025-10-25, release date: 2026-07-22)

Primary citation

Hao, Q.,Wang, L.,Pan, H.,Xiao, X.,Dong, W.,Pan, W.,Sun, J.,Su, W.,Fang, L.,Park, E.,Yao, G.
Structure-based design of Sec61 translocon targeting prodrugs minimize off-target toxicity.
Cell Chem Biol, 33:823-836.e21, 2026

PubMed Abstract: 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 Å 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.

PubMed: 42263680
DOI: 10.1016/j.chembiol.2026.05.006

Experimental method

ELECTRON MICROSCOPY (3.1 Å)