Structural basis for translocon modulation
EMSL Project ID
51245
Abstract
Nearly 95% of human secretory and integral membrane proteins are cotranslationally targeted to the Sec61 translocon, which facilitates transport of these proteins into the ER lumen or lipid bilayer. We previously characterized potent inhibitors of secretory protein biogenesis that directly target Sec61. These small molecules represent valuable tools for studying the complicated protein translocation process given their distinct mechanisms, which may be signal peptide-discriminatory and hence substrate selective or substrate-nonselective. Further, inhibitors of Sec61 can serve as lead molecules for anticancer therapeutic development. Earlier structural work used single particle Cryo-EM to reveal Sec61 bound to the mammalian ribosome in various states. However, no structures of Sec61 bound to a small molecule inhibitor exist so far. We have recently identified a natural product, coibamide A (CbA), that potently inhibits cell proliferation, migration and invasive capacity, and in early assessments of in vivo activity, inhibited tumor growth in subcutaneous xenograft models of human glioblastoma and breast cancer. However, current lack of structural insights into potent Sec61 inhibition by CbA hamper structure-guided optimization efforts. Here, we aim to determine the binding mode of CbA towards detergent-solubilized Sec61. This work is expected to identify a minimal chemical module required for potent targeting of Sec61 as a means to modulate secretory protein flux through the ER and facilitate future discovery of selective cancer therapeutics.
Project Details
Start Date
2020-01-15
End Date
2021-03-17
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members