2BFO

Leishmania major pteridine reductase 1 in complex with NADPH

2BFO の概要

• エントリーDOI: 10.2210/pdb2bfo/pdb
• 関連するPDBエントリー: 2BF7 2BFA 2BFM 2BFP
• 分子名称: PTERIDINE REDUCTASE 1, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: pteridine reductase, trypanosomatids, drug resistance, pterin salvage, short-chain dehydrogenase/reductase, methotrexate resistance, nadp, oxidoreductase
• 由来する生物種: LEISHMANIA MAJOR
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 125116.41

構造登録者

Schuettelkopf, A.W.,Hunter, W.N. (登録日: 2004-12-10, 公開日: 2005-08-31, 最終更新日: 2023-12-13)

主引用文献

Schuettelkopf, A.W.,Hardy, L.W.,Beverley, S.M.,Hunter, W.N.
Structures of Leishmania Major Pteridine Reductase Complexes Reveal the Active Site Features Important for Ligand Binding and to Guide Inhibitor Design
J.Mol.Biol., 352:105-, 2005

PubMed Abstract: Pteridine reductase (PTR1) is an NADPH-dependent short-chain reductase found in parasitic trypanosomatid protozoans. The enzyme participates in the salvage of pterins and represents a target for the development of improved therapies for infections caused by these parasites. A series of crystallographic analyses of Leishmania major PTR1 are reported. Structures of the enzyme in a binary complex with the cofactor NADPH, and ternary complexes with cofactor and biopterin, 5,6-dihydrobiopterin, and 5,6,7,8-tetrahydrobiopterin reveal that PTR1 does not undergo any major conformational changes to accomplish binding and processing of substrates, and confirm that these molecules bind in a single orientation at the catalytic center suitable for two distinct reductions. Ternary complexes with cofactor and CB3717 and trimethoprim (TOP), potent inhibitors of thymidylate synthase and dihydrofolate reductase, respectively, have been characterized. The structure with CB3717 reveals that the quinazoline moiety binds in similar fashion to the pterin substrates/products and dominates interactions with the enzyme. In the complex with TOP, steric restrictions enforced on the trimethoxyphenyl substituent prevent the 2,4-diaminopyrimidine moiety from adopting the pterin mode of binding observed in dihydrofolate reductase, and explain the inhibition properties of a range of pyrimidine derivates. The molecular detail provided by these complex structures identifies the important interactions necessary to assist the structure-based development of novel enzyme inhibitors of potential therapeutic value.

PubMed: 16055151
DOI: 10.1016/J.JMB.2005.06.076

実験手法

X-RAY DIFFRACTION (2.6 Å)