7SB7

Crystal structure of T. brucei hypoxanthine guanine phosphoribosyltransferase in complex with (4S,7S)-7-hydroxy-4-((guanin-9-yl)methyl)-2,5-dioxaheptan-1,7-diphosphonate

7SB7 の概要

• エントリーDOI: 10.2210/pdb7sb7/pdb
• 分子名称: Hypoxanthine-guanine phosphoribosyltransferase, ({(2S)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-2-[(2S)-2-hydroxy-2-phosphonoethoxy]propoxy}methyl)phosphonic acid (3 entities in total)
• 機能のキーワード: inhibitor, complex, phosphonate, purine, transferase
• 由来する生物種: Trypanosoma brucei brucei
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 49330.04

構造登録者

Guddat, L.W.,Keough, D.T. (登録日: 2021-09-24, 公開日: 2022-03-02, 最終更新日: 2023-10-18)

主引用文献

Klejch, T.,Keough, D.T.,King, G.,Dolezelova, E.,Cesnek, M.,Budesinsky, M.,Zikova, A.,Janeba, Z.,Guddat, L.W.,Hockova, D.
Stereo-Defined Acyclic Nucleoside Phosphonates are Selective and Potent Inhibitors of Parasite 6-Oxopurine Phosphoribosyltransferases.
J.Med.Chem., 65:4030-4057, 2022

PubMed Abstract: Pathogens such as and spp. are unable to synthesize purine nucleobases. They rely on the salvage of these purines and their nucleosides from the host cell to synthesize the purine nucleotides required for DNA/RNA production. The key enzymes in this pathway are purine phosphoribosyltransferases (PRTs). Here, we synthesized 16 novel acyclic nucleoside phosphonates, 12 with a chiral center at C-2', and eight bearing a second chiral center at C-6'. Of these, bisphosphonate (,)- is the most potent inhibitor of the and 6-oxopurine PRTs and the most potent inhibitor of two () 6-oxopurine PRTs yet discovered, with values as low as 2 nM. Crystal structures of (,)- in complex with human and 6-oxopurine PRTs show that the inhibitor binds to the enzymes in different conformations, providing an explanation for its potency and selectivity (, 35-fold in favor of the parasite enzymes).

PubMed: 35175749
DOI: 10.1021/acs.jmedchem.1c01881

実験手法

X-RAY DIFFRACTION (2.64716619036 Å)