AI Article Synopsis
- The nucleotide exchange factor SOS plays a key role in activating RAS by switching it from an inactive GDP-bound state to an active GTP-bound state.
- Recently discovered small-molecule allosteric activators of SOS1 can enhance RAS-GTP levels in cells and inhibit ERK phosphorylation at higher concentrations through a feedback mechanism.
- Further research involved using NMR-based fragment screening and structure-based design to create improved compounds that boost SOS1 activity on RAS and align with earlier findings.
Article Abstract
The nucleotide exchange factor Son of Sevenless (SOS) catalyzes the activation of RAS by converting it from its inactive GDP-bound state to its active GTP-bound state. Recently, we have reported the discovery of small-molecule allosteric activators of SOS1 that can increase the amount of RAS-GTP in cells. The compounds can inhibit ERK phosphorylation at higher concentrations by engaging a feedback mechanism. To further study this process, we sought different chemical matter from an NMR-based fragment screen using selective methyl labeling. To aid this process, several Ile methyl groups located in different binding sites of the protein were assigned and used to categorize the NMR hits into different classes. Hit to lead optimization using an iterative structure-based design paradigm resulted in compounds with improvements in binding affinity. These improved molecules of a different chemical class increase SOS1-mediated nucleotide exchange on RAS and display cellular action consistent with our prior results.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acs.jmedchem.0c00511 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The Role of Mitochondrial Solute Carriers SLC25 in Cancer Metabolic Reprogramming: Current Insights and Future Perspectives.
Int J Mol Sci
December 2024
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy.
Cancer cells undergo remarkable metabolic changes to meet their high energetic and biosynthetic demands. The Warburg effect is the most well-characterized metabolic alteration, driving cancer cells to catabolize glucose through aerobic glycolysis to promote proliferation. Another prominent metabolic hallmark of cancer cells is their increased reliance on glutamine to replenish tricarboxylic acid (TCA) cycle intermediates essential for ATP production, aspartate and fatty acid synthesis, and maintaining redox homeostasis.
View Article and Find Full Text PDFTemperature Regulates Astroglia Morphogenesis Through Thermosensory Circuitry in Caenorhabditis elegans.
Glia
January 2025
State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science and Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai, P. R. China.
Astrocytes are the most abundant type of macroglia in the brain and play crucial roles in regulating neural development and functions. The diverse functions of astrocytes are largely determined by their morphology, which is regulated by genetic and environmental factors. However, whether and how the astrocyte morphology is affected by temperature remains largely unknown.
View Article and Find Full Text PDFBiochemical and structural characterization of Rab3GAP reveals insights into Rab18 nucleotide exchange activity.
Nat Commun
January 2025
Life Sciences Institute, Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
The heterodimeric Rab3GAP complex is a guanine nucleotide exchange factor (GEF) for the Rab18 GTPase that regulates lipid droplet metabolism, ER-to-Golgi trafficking, secretion, and autophagy. Why both subunits of Rab3GAP are required for Rab18 GEF activity and the molecular basis of how Rab3GAP engages and activates its cognate substrate are unknown. Here we show that human Rab3GAP is conformationally flexible and potentially autoinhibited by the C-terminal domain of its Rab3GAP2 subunit.
View Article and Find Full Text PDFRas S89D mutation induced allosteric changes that promoted its nucleotide exchange and signaling activation.
Int J Biol Macromol
January 2025
Department of Pulmonary and Critical Care Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China. Electronic address:
The small GTPase Ras is among the most frequently mutated genes and its mutations often drive oncogenesis across various cancers. While the role of NRas phosphorylation at S89 in the context of a Q61R mutation in melanoma genesis remains controversial, the impact of S89 phosphorylation on NRas function has not been fully elucidated. In this study, we employed the S89D phosphorylation-mimetic mutation and demonstrated that the S89D mutation alone activated all Ras isoforms by increasing the GTP-bound population, thereby promoting ERK phosphorylation and cell proliferation.
View Article and Find Full Text PDFRabin8 phosphorylated by NDR2/STK38L, the canine early retinal degeneration (erd) gene product, directs rhodopsin Golgi-to-cilia trafficking.
J Cell Sci
January 2025
Department of Ophthalmology and Visual Sciences, University of New Mexico, Albuquerque, New Mexico 87131, Mexico.
The Rab11-Rabin8-Rab8 ciliogenesis complex regulates the expansion of cilia-derived light-sensing organelles, the rod outer segments, via post-Golgi rhodopsin transport carriers (RTCs). Rabin8, an effector of Rab11 and a nucleotide exchange factor (GEF) for Rab8, is phosphorylated at S272 by NDR2 kinase (aka STK38L), a canine erd gene product linked to the human ciliopathy Leber congenital amaurosis (LCA). Here, we define the step at which NDR2 phosphorylated Rabin8 regulates Rab11-Rab8 succession in X.
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!