2C7V

Structure of Trypanosoma brucei pteridine reductase (PTR1) in ternary complex with cofactor and the antifolate methotrexate

2C7V の概要

• エントリーDOI: 10.2210/pdb2c7v/pdb
• 分子名称: PTERIDINE REDUCTASE, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, METHOTREXATE, ... (6 entities in total)
• 機能のキーワード: pteridine reductase, trypanosomatids, drug resistance, short-chain dehydrogenase/reductase, methotrexate resistance, oxidoreductase
• 由来する生物種: TRYPANOSOMA BRUCEI BRUCEI
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 119980.47

構造登録者

Dawson, A.,Gibellini, F.,Sienkiewicz, N.,Fyfe, P.K.,McLuskey, K.,Fairlamb, A.H.,Hunter, W.N. (登録日: 2005-11-29, 公開日: 2006-09-19, 最終更新日: 2024-11-13)

主引用文献

Dawson, A.,Gibellini, F.,Sienkiewicz, N.,Tulloch, L.B.,Fyfe, P.K.,Mcluskey, K.,Fairlamb, A.H.,Hunter, W.N.
Structure and Reactivity of Trypanosoma Brucei Pteridine Reductase: Inhibition by the Archetypal Antifolate Methotrexate
Mol.Microbiol., 61:1457-, 2006

PubMed Abstract: The protozoan Trypanosoma brucei has a functional pteridine reductase (TbPTR1), an NADPH-dependent short-chain reductase that participates in the salvage of pterins, which are essential for parasite growth. PTR1 displays broad-spectrum activity with pterins and folates, provides a metabolic bypass for inhibition of the trypanosomatid dihydrofolate reductase and therefore compromises the use of antifolates for treatment of trypanosomiasis. Catalytic properties of recombinant TbPTR1 and inhibition by the archetypal antifolate methotrexate have been characterized and the crystal structure of the ternary complex with cofactor NADP+ and the inhibitor determined at 2.2 A resolution. This enzyme shares 50% amino acid sequence identity with Leishmania major PTR1 (LmPTR1) and comparisons show that the architecture of the cofactor binding site, and the catalytic centre are highly conserved, as are most interactions with the inhibitor. However, specific amino acid differences, in particular the placement of Trp221 at the side of the active site, and adjustment of the beta6-alpha6 loop and alpha6 helix at one side of the substrate-binding cleft significantly reduce the size of the substrate binding site of TbPTR1 and alter the chemical properties compared with LmPTR1. A reactive Cys168, within the active site cleft, in conjunction with the C-terminus carboxyl group and His267 of a partner subunit forms a triad similar to the catalytic component of cysteine proteases. TbPTR1 therefore offers novel structural features to exploit in the search for inhibitors of therapeutic value against African trypanosomiasis.

PubMed: 16968221
DOI: 10.1111/J.1365-2958.2006.05332.X

実験手法

X-RAY DIFFRACTION (2.2 Å)