Nucleic Acids Research Advance Access published online on October 24, 2006
Nucleic Acids Research, doi:10.1093/nar/gkl747
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Structural Biology |
Mimicking damaged DNA with a small molecule inhibitor of human UNG2
Department of Pharmacology and Molecular Sciences 725 North Wolfe Street, Baltimore, MD 21205, USA 1 Department of Biophysics and Biophysical Chemistry of the Johns Hopkins Medical School 725 North Wolfe Street, Baltimore, MD 21205, USA
*To whom correspondence should be addressed. Tel: +1 410 502 2758; Fax: +1 410 955 3023; Email: jstivers{at}jhmi.edu
Received September 5, 2006. Revised September 22, 2006. Accepted September 26, 2006.
Human nuclear uracil DNA glycosylase (UNG2) is a cellular DNA repair enzyme that is essential for a number of diverse biological phenomena ranging from antibody diversification to B-cell lymphomas and type-1 human immunodeficiency virus infectivity. During each of these processes, UNG2 recognizes uracilated DNA and excises the uracil base by flipping it into the enzyme active site. We have taken advantage of the extrahelical uracil recognition mechanism to build large small-molecule libraries in which uracil is tethered via flexible alkane linkers to a collection of secondary binding elements. This high-throughput synthesis and screening approach produced two novel uracil-tethered inhibitors of UNG2, the best of which was crystallized with the enzyme. Remarkably, this inhibitor mimics the crucial hydrogen bonding and electrostatic interactions previously observed in UNG2 complexes with damaged uracilated DNA. Thus, the environment of the binding site selects for library ligands that share these DNA features. This is a general approach to rapid discovery of inhibitors of enzymes that recognize extrahelical damaged bases.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L. A. Seiple, J. H. Cardellina II, R. Akee, and J. T. Stivers Potent Inhibition of Human Apurinic/Apyrimidinic Endonuclease 1 by Arylstibonic Acids Mol. Pharmacol., March 1, 2008; 73(3): 669 - 677. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. S. Pettersen, O. Sundheim, K. M. Gilljam, G. Slupphaug, H. E. Krokan, and B. Kavli Uracil-DNA glycosylases SMUG1 and UNG2 coordinate the initial steps of base excision repair by distinct mechanisms Nucleic Acids Res., June 9, 2007; 35(12): 3879 - 3892. [Abstract] [Full Text] [PDF]
|
|