title: Inhibition of Leishmania major pteridine reductase by 2,4,6-triaminoquinazoline: structure of the NADPH ternary complex.
abstract: The structure of Leishmania major pteridine reductase (PTR1) in complex with NADPH and the inhibitor 2,4,6-triaminoquinazoline (TAQ) has been solved in a new crystal form by molecular replacement and refined to 2.6 A resolution. The inhibitor mimics a fragment, the pterin head group, of the archetypal antifolate drug methotrexate (MTX) and exploits similar chemical features to bind in the PTR1 active site. Despite being a much smaller molecule, TAQ displays a similar inhibition constant to that of MTX. PTR1 is a target for the development of improved therapies for infections caused by trypanosomatid parasites and this analysis provides information to assist the structure-based development of novel enzyme inhibitors.
authors.affiliation: Division of Biological Chemistry and Molecular Microbiology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland.
authors.forename: Karen
authors.initials: K
authors.lastname: McLuskey
authors.forename: Federica
authors.initials: F
authors.lastname: Gibellini
authors.forename: Paulo
authors.initials: P
authors.lastname: Carvalho
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Avery
authors.forename: William N
authors.initials: WN
authors.lastname: Hunter
mesh_terms: D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004583:Electrons; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006860:Hydrogen Bonding; D018320:Leishmania major / Q000201:enzymology*; D008727:Methotrexate / Q000494:pharmacology; D008956:Models, Chemical; D008958:Models, Molecular; D009249:NADP / Q000737:chemistry*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011487:Protein Conformation; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D011799:Quinazolines; C026010:2,4,6-triamino-5-chloroquinazoline; D009249:NADP; D010088:Oxidoreductases; C085592:pteridine reductase; D008727:Methotrexate