Angew Chem Int Ed Engl
December 2024
Peptide stapling has emerged as a versatile approach in drug discovery to reinforce secondary structure elements especially α-helices and improve properties of linear bioactive peptides. Inspired by the prevalence of arginine in protein-protein and protein-DNA interfaces, we investigated guanidinium-stapling as a means to constrain helical peptides. Guanidinium stapling was readily achieved on solid support, utilizing two orthogonally protected lysine or unatural α-amino acid residues with an amino function.
View Article and Find Full Text PDFSignalosomes are high-order protein machineries involved in complex mechanisms controlling regulated immune defense and cell death execution. The immune response is initiated by the recognition of exogeneous or endogenous signals, triggering the signalosome assembly process. The final step of signalosome fate often involves membrane-targeting and activation of pore-forming execution domains, leading to membrane disruption and ultimately cell death.
View Article and Find Full Text PDF2-iminoacetate synthase ThiH is a radical S-adenosyl-L-methionine (SAM) L-tyrosine lyase and catalyzes the L-tyrosine Cα-Cβ bond break to produce dehydroglycine and p-cresol while the radical SAM L-tryptophan lyase NosL cleaves the L-tryptophan Cα-C bond to produce 3-methylindole-2-carboxylic acid. It has been difficult to understand the features that condition one C-C bond break over the other one because the two enzymes display significant primary structure similarities and presumably similar substrate-binding modes. Here, we report the crystal structure of L-tyrosine bound ThiH from Thermosinus carboxydivorans revealing an unusual protonation state of L-tyrosine upon binding.
View Article and Find Full Text PDFThe radical S-adenosyl-l-methionine tryptophan lyase uses radical-based chemistry to convert l-tryptophan into 3-methyl-2-indolic acid, a fragment in the biosynthesis of the thiopeptide antibiotic nosiheptide. This complex reaction involves several successive steps corresponding to (i) the activation by a specific hydrogen-atom abstraction, (ii) an unprecedented •CO radical migration, (iii) a cyanide fragment release, and (iv) the termination of the radical-based reaction. In vitro study of this reaction is made more difficult because the enzyme produces a significant amount of a shunt product instead of the natural product.
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