AI Article Synopsis
- - The Sec61 translocon is critical for transporting newly formed proteins into the endoplasmic reticulum or embedding them in its membrane.
- - Recent discoveries in structural biology have provided insight into how Sec61 interacts with other proteins and have identified small molecules that can inhibit its function.
- - Some of these molecules can selectively block the transport of specific proteins, suggesting potential strategies for targeting Sec61 in drug development while minimizing harmful effects.
Article Abstract
The Sec61 translocon mediates the translocation of numerous, newly synthesized precursor proteins into the lumen of the endoplasmic reticulum or their integration into its membrane. Recently, structural biology revealed conformations of idle or substrate-engaged Sec61, and likewise its interactions with the accessory membrane proteins Sec62, Sec63, and TRAP, respectively. Several natural and synthetic small molecules have been shown to block Sec61-mediated protein translocation. Since this is a key step in protein biogenesis, broad inhibition is generally cytotoxic, which may be problematic for a putative drug target. Interestingly, several compounds exhibit client-selective modes of action, such that only translocation of certain precursor proteins was affected. Here, we discuss recent advances of structural biology, molecular modelling, and molecular screening that aim to use Sec61 as feasible drug target.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11695074 | PMC |
| http://dx.doi.org/10.1002/jmr.3108 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Protein translocation across cellular membranes is an essential and nano-scale dynamic process. In the bacterial cytoplasmic membrane, the core proteins in this process are a membrane protein complex, SecYEG, corresponding to the eukaryotic Sec61 complex, and a cytoplasmic protein, SecA ATPase. Despite more than three decades of extensive research on Sec proteins, from genetic experiments to cutting-edge single-molecule analyses, no study has visually demonstrated protein translocation.
View Article and Find Full Text PDFExploring Mycolactone-The Unique Causative Toxin of Buruli Ulcer: Biosynthetic, Synthetic Pathways, Biomarker for Diagnosis, and Therapeutic Potential.
Toxins (Basel)
December 2024
Department of Chemistry, University of Ghana, Legon-Accra P.O. Box LG56, Ghana.
Mycolactone is a complex macrolide toxin produced by , the causative agent of Buruli ulcer. The aim of this paper is to review the chemistry, biosynthetic, and synthetic pathways of mycolactone A/B to help develop an understanding of the mode of action of these polyketides as well as their therapeutic potential. The synthetic work has largely been driven by the desire to afford researchers enough (≥100 mg) of the pure toxins for systematic biological studies toward understanding their very high biological activities.
View Article and Find Full Text PDFCutting-edge Bioinformatics strategies for synthesizing Cyclotriazadisulfonamide (CADA) analogs in next-Generation HIV therapies.
Sci Rep
November 2024
Department of Biochemistry, College of Allied Sciences, De La Salle Medical and Health Sciences Institute, City of Dasmariñas, Cavite, 4114, Philippines.
Cyclotriazadisulfonamide (CADA) is a macrocyclic compound known for its unique mechanism in inhibiting HIV infection by downregulating the CD4 T-cell receptor, a crucial entry point for the virus. Unlike other antiretrovirals, CADA exhibits activity against a wide range of HIV strains, as all HIV variants require CD4 binding for infection. Furthermore, CADA has shown a synergistic effect with clinically approved anti-HIV drugs, offering potential for enhanced therapeutic strategies (Vermeire & Schols, [65]).
View Article and Find Full Text PDFProtein translocation through α-helical channels and insertases.
Structure
January 2025
State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China. Electronic address:
Protein translocation systems are essential for distributing proteins across various lipid membranes in cells. Cellular membranes, such as the endoplasmic reticulum (ER) membrane and mitochondrial inner membrane, require highly regulated protein translocation machineries that specifically allow the passage of protein polypeptides while blocking smaller molecules like ions and water. Key translocation systems include the Sec translocation channel, the protein insertases of the Oxa1 superfamily, and the translocases of the mitochondrial inner membrane (TIM).
View Article and Find Full Text PDFAlternate MHC I Antigen Presentation Pathways Allow CD8+ T-cell Recognition and Killing of Cancer Cells in the Absence of β2M or TAP.
Cancer Immunol Res
January 2025
Department of Pathology, UMass Chan Medical School, Worcester, Massachusetts.
MHC I antigen presentation allows CD8+ T cells to detect and eliminate cancerous or virally infected cells. The MHC I pathway is not essential for cell growth and viability, so cancers and viruses can evade control by CD8+ T cells by inactivating antigen presentation. In cancers, two common ways for this evasion are the loss of either the MHC I light chain [β2 microglobulin (β2M)] or the transporter-associated with antigen processing (TAP).
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!