Publications by authors named "S R Vaithiyalingam"
Phase separation compartmentalizes many cellular pathways. Given that the same interactions that drive phase separation mediate the formation of soluble complexes below the saturation concentration, the contribution of condensates versus complexes to function is sometimes unclear. Here, we characterized several new cancer-associated mutations of the tumor suppressor speckle-type POZ protein (SPOP), a substrate recognition subunit of the Cullin3-RING ubiquitin ligase.
View Article and Find Full Text PDFPhase separation is a ubiquitous process that compartmentalizes many cellular pathways. Given that the same interactions that drive phase separation mediate the formation of complexes below the saturation concentration, the contribution of condensates vs complexes to function is not always clear. Here, we characterized several new cancer-associated mutations of the tumor suppressor Speckle-type POZ protein (SPOP), a substrate recognition subunit of the Cullin3-RING ubiquitin ligase (CRL3), which pointed to a strategy for generating separation-of-function mutations.
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- E3 ligases play a critical role in regulating proteins that have terminal destabilizing motifs (degrons), but how they distinguish true substrates from similar proteins remains unclear.
- The study focuses on KLHDC2, which targets specific Gly-Gly degrons and exhibits a unique dual assembly model that influences its substrate binding and E3 ligase activation.
- KLHDC2's ability to form a self-inactivated tetramer and its interaction with true substrates helps ensure that only appropriate proteins are marked for degradation, effectively acting as a molecular timer that prevents E3 inactivation until the right targets are identified.
Chemical scaffold recycling: Structure-guided conversion of an HIV integrase inhibitor into a potent influenza virus RNA-dependent RNA polymerase inhibitor designed to minimize resistance potential.
Eur J Med Chem
February 2023
Article Synopsis
- Influenza remains a major cause of death globally, leading to efforts to develop antiviral strategies that have been met with resistance from the virus, including resistance to the new drug baloxavir marboxil.
- Researchers have leveraged structural insights from endonuclease-substrate complexes to design new inhibitor molecules that specifically target the endonuclease, aiming to minimize the chances of resistance mutations.
- The team successfully created potent inhibitors effective against both normal and resistant strains of the endonuclease, including macrocyclic versions, and also identified ways to enhance the effectiveness of these cyclic compounds based on structural analysis.
Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic Paired Box 3-Forkhead Box O1 (PAX3-FOXO1) fusion protein, which governs a core regulatory circuitry transcription factor network. Here, we show that the histone lysine demethylase 4B (KDM4B) is a therapeutic vulnerability for PAX3-FOXO1 RMS.
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