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Crystal Structures of Acyclic Nucleoside Phosphonates in Complex with Escherichia coli Hypoxanthine Phosphoribosyltransferase
Author(s) -
Eng Wai Soon,
Hocková Dana,
Špaček Petr,
Baszczyňski Ondřej,
Janeba Zlatko,
Naesens Lieve,
Keough Dianne T.,
Guddat Luke W.
Publication year - 2016
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201601679
Subject(s) - nucleotide salvage , phosphoribosyltransferase , hypoxanthine , hypoxanthine guanine phosphoribosyltransferase , escherichia coli , purine nucleoside phosphorylase , purine , biochemistry , rational design , purine metabolism , chemistry , xanthine , biology , nucleoside , enzyme , nucleotide , genetics , gene , mutant
Drug resistant uropathogenic E. coli associated with urinary tract infections (UTIs) are a serious and debilitating health threat. Therefore new drug targets to treat this disease need to be explored. One possible approach is to block the synthesis of the nucleoside monophosphates required for DNA/RNA production in these pathogens. In E. coli , the purine salvage pathway has two 6‐oxopurine phosphoribosyltransferases (PRTs), xanthine‐guanine PRT ( Ec XGPRT) and hypoxanthine PRT ( Ec HPRT). Here, we investigate acyclic nucleoside phosphonates (ANPs) as inhibitors of Ec HPRT and have determined six crystal structures of Ec HPRT in complex with ANPs. These data reveal the binding modes of these compounds and can assist in future rational structure‐based design efforts. It is suggested that a combination of inhibitors that block de novo and salvage pathways is a plausible approach to developing new antibiotics for E. coli UTIs. In addition, we provide details of a novel approach to accelerating the crystallization of this enzyme that may be of general applicability for rational drug discovery.