Open AccessInhibition of Leishmania major pteridine reductase by 2,4,6‐triaminoquinazoline: structure of the NADPH ternary complex
Author(s) -
McLuskey Karen,
Gibellini Federica,
Carvalho Paulo,
Avery Mitchell A.,
Hunter William N.
Publication year - 2004
Publication title -
acta crystallographica section d
Language(s) - English
Resource type - Journals
ISSN - 1399-0047
DOI - 10.1107/s0907444904018955
Subject(s) - pteridine , pterin , chemistry , biochemistry , enzyme , stereochemistry , ternary complex , cofactor
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 Å 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.