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The crystal structure of inhibitor-15 covalently bound to PDE6DThe crystal structure of inhibitor-15 covalently bound to PDE6D
Structural highlights
FunctionPDE6D_HUMAN Acts as a GTP specific dissociation inhibitor (GDI). Increases the affinity of ARL3 for GTP by several orders of magnitude and does so by decreasing the nucleotide dissociation rate. Stabilizes Arl3-GTP by decreasing the nucleotide dissociation (By similarity). Publication Abstract from PubMedCovalent labeling of amino acids in proteins by reactive small molecules, in particular at cysteine SH and lysine NH groups, is a powerful approach to identify and characterize proteins and their functions. However, for the less-reactive carboxylic acids present in Asp and Glu, hardly any methodology is available. Employing the lipoprotein binding chaperone PDE6delta as an example, we demonstrate that incorporation of isoxazolium salts that resemble the structure and reactivity of Woodward's reagent K into protein ligands provides a novel method for selective covalent targeting of binding site carboxylic acids in whole proteomes. Covalent adduct formation occurs via rapid formation of enol esters and the covalent bond is stable even in the presence of strong nucleophiles. This new method promises to open up hitherto unexplored opportunities for chemical biology research. Covalent Protein Labeling at Glutamic Acids.,Martin-Gago P, Fansa EK, Winzker M, Murarka S, Janning P, Schultz-Fademrecht C, Baumann M, Wittinghofer A, Waldmann H Cell Chem Biol. 2017 Apr 13. pii: S2451-9456(17)30098-3. doi:, 10.1016/j.chembiol.2017.03.015. PMID:28434875[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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