Covalent Fragment Inhibits RhoA Activation by Guanine Exchange Factors.
Autor: | Hussain MS; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States., Liu D; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States., Alilain WJ; Spinal Cord and Brain Injury Center, University of Kentucky, Lexington, Kentucky 40506, United States., Meroueh SO; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States. |
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Jazyk: | angličtina |
Zdroj: | ACS chemical neuroscience [ACS Chem Neurosci] 2023 Jul 19; Vol. 14 (14), pp. 2509-2516. Date of Electronic Publication: 2023 Jun 29. |
DOI: | 10.1021/acschemneuro.3c00154 |
Abstrakt: | Ras homolog gene family member (RhoA) is a GTPase and a member of the RAS superfamily of GTPases. RhoA is a master regulator of the actin cytoskeleton. It inhibits axon growth preventing repair and recovery following spinal cord and traumatic brain injuries. Despite decades of research into the biological function of Rho GTPases, there exist no small-molecule Rho inhibitors. Here, we screen a library of cysteine electrophiles to explore whether covalent bond formation at Cys-107 leads to inhibition of RhoA activation by guanine exchange factor Trio. Two fragments, propiolamide 1 (ACR-895) and acrylamide 2 (ACR-917), inhibited RhoA nucleotide exchange by Trio in a time-dependent manner. The fragments formed a covalent bond with wild-type RhoA but not Cys107Ser RhoA mutant. Time- and concentration-dependent studies led to equilibrium constants K |
Databáze: | MEDLINE |
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