8c3n
Stapled peptide SP30 in complex with humanised RadA mutant HumRadA22Stapled peptide SP30 in complex with humanised RadA mutant HumRadA22
Structural highlights
FunctionRADA_PYRFU Involved in DNA repair and in homologous recombination. Binds and assemble on single-stranded DNA to form a nucleoprotein filament. Hydrolyzes ATP in a ssDNA-dependent manner and promotes DNA strand exchange between homologous DNA molecules. Publication Abstract from PubMedStapling is a macrocyclisation method that connects amino acid side chains of a peptide to improve its pharmacological properties. We describe an approach for stapled peptide preparation and biochemical evaluation that combines recombinant expression of fusion constructs of target peptides and cysteine-reactive divinyl-heteroaryl chemistry as an alternative to solid-phase synthesis. We then employ this workflow to prepare and evaluate BRC-repeat-derived inhibitors of the RAD51 recombinase, showing that a diverse range of secondary structure elements in the BRC repeat can be stapled without compromising binding and function. Using X-ray crystallography, we elucidate the atomic-level features of the staple moieties. We then demonstrate that BRC-repeat-derived stapled peptides can disrupt RAD51 function in cells following ionising radiation treatment. A recombinant approach for stapled peptide discovery yields inhibitors of the RAD51 recombinase.,Pantelejevs T, Zuazua-Villar P, Koczy O, Counsell AJ, Walsh SJ, Robertson NS, Spring DR, Downs JA, Hyvonen M Chem Sci. 2023 Nov 21;14(47):13915-13923. doi: 10.1039/d3sc03331g. eCollection , 2023 Dec 6. PMID:38075664[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||