Recifin A, Initial Example of the Tyr-Lock Peptide Structural Family, Is a Selective Allosteric Inhibitor of Tyrosyl-DNA Phosphodiesterase I.

Autor: Krumpe LRH; Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, United States.; Molecular Targets Program, Center for Cancer Research, NCI-Frederick, NIH, Frederick, Maryland 21702, United States., Wilson BAP; Molecular Targets Program, Center for Cancer Research, NCI-Frederick, NIH, Frederick, Maryland 21702, United States., Marchand C; Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, NCI, NIH, Bethesda, Maryland 20892, United States., Sunassee SN; Molecular Targets Program, Center for Cancer Research, NCI-Frederick, NIH, Frederick, Maryland 21702, United States., Bermingham A; Molecular Targets Program, Center for Cancer Research, NCI-Frederick, NIH, Frederick, Maryland 21702, United States., Wang W; Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, NCI, NIH, Bethesda, Maryland 20892, United States., Price E; Molecular Targets Program, Center for Cancer Research, NCI-Frederick, NIH, Frederick, Maryland 21702, United States., Guszczynski T; Molecular Targets Program, Center for Cancer Research, NCI-Frederick, NIH, Frederick, Maryland 21702, United States., Kelley JA; Chemical Biology Laboratory, Center for Cancer Research, NCI-Frederick, NIH, Frederick, Maryland 21702, United States., Gustafson KR; Molecular Targets Program, Center for Cancer Research, NCI-Frederick, NIH, Frederick, Maryland 21702, United States., Pommier Y; Developmental Therapeutics Branch, Laboratory of Molecular Pharmacology, NCI, NIH, Bethesda, Maryland 20892, United States., Rosengren KJ; School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia., Schroeder CI; Chemical Biology Laboratory, Center for Cancer Research, NCI-Frederick, NIH, Frederick, Maryland 21702, United States.; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., O'Keefe BR; Molecular Targets Program, Center for Cancer Research, NCI-Frederick, NIH, Frederick, Maryland 21702, United States.; Natural Products Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick, Maryland 21702, United States.
Jazyk: angličtina
Zdroj: Journal of the American Chemical Society [J Am Chem Soc] 2020 Dec 16; Vol. 142 (50), pp. 21178-21188. Date of Electronic Publication: 2020 Dec 02.
DOI: 10.1021/jacs.0c10418
Abstrakt: Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a molecular target for the sensitization of cancer cells to the FDA-approved topoisomerase inhibitors topotecan and irinotecan. High-throughput screening of natural product extract and fraction libraries for inhibitors of TDP1 activity resulted in the discovery of a new class of knotted cyclic peptides from the marine sponge Axinella sp. Bioassay-guided fractionation of the source extract resulted in the isolation of the active component which was determined to be an unprecedented 42-residue cysteine-rich peptide named recifin A. The native NMR structure revealed a novel fold comprising a four strand antiparallel β-sheet and two helical turns stabilized by a complex disulfide bond network that creates an embedded ring around one of the strands. The resulting structure, which we have termed the Tyr-lock peptide family, is stabilized by a tyrosine residue locked into three-dimensional space. Recifin A inhibited the cleavage of phosphodiester bonds by TDP1 in a FRET assay with an IC 50 of 190 nM. Enzyme kinetics studies revealed that recifin A can specifically modulate the enzymatic activity of full-length TDP1 while not affecting the activity of a truncated catalytic domain of TDP1 lacking the N-terminal regulatory domain (Δ1-147), suggesting an allosteric binding site for recifin A on the regulatory domain of TDP1. Recifin A represents both the first of a unique structural class of knotted disulfide-rich peptides and defines a previously unseen mechanism of TDP1 inhibition that could be productively exploited for potential anticancer applications.
Databáze: MEDLINE
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