Recifin A, Initial Example of the Tyr-Lock Peptide Structural Family, Is a Selective Allosteric Inhibitor of Tyrosyl-DNA Phosphodiesterase I
Lauren R. H. Krumpe, Brice A. P. Wilson, Christophe Marchand, Suthananda N. Sunassee, Alun Bermingham, Wenjie Wang, Edmund V. Price, Tad Guszczynski, James A. Kelley, Kirk R. Gustafson, Yves Pommier, K. Johan Rosengren, Christina I. Schroeder, Barry R. O’Keefe
Abstract
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.