Journal
MOLECULAR CELL
Volume 5, Issue 6, Pages 1035-1041Publisher
CELL PRESS
DOI: 10.1016/S1097-2765(00)80268-3
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Funding
- NIGMS NIH HHS [GM46330] Funding Source: Medline
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Type IB topoisomerases and tyrosine recombinases are structurally homologous strand transferases that act through DNA-(3'-phosphotyrosyl)-enzyme intermediates. A constellation of conserved amino acids (Arg-130, Lys-167, Arg-223, and His-265 in vaccinia topoisomerase) catalyzes transesterification of tyrosine to the scissile phosphodiester. We used 8'-bridging phosphorothiolate-modified DNAs to implicate Lys-167 as a general acid catalyst. The lower pK(a), of the 5'-S leaving group versus 5'-O restored activity to the K167A mutant, whereas there was no positive thio effect for mutants R223A and H265A. The lysine is located atop a flexible hairpin loop, and it shifts into the minor groove upon DNA binding. Coupling of conformational changes in a general acid loop to covalent catalysis of phosphoryl transfer is one of several mechanistic features shared by the topoisomerase/recombinase and protein phosphatase superfamilies.
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