4RHX

Structures of Mycobacterium tuberculosis 6-oxopurine phosphoribosyltransferase which is a potential target for drug development against this disease

4RHX の概要

• エントリーDOI: 10.2210/pdb4rhx/pdb
• 分子名称: Hypoxanthine-guanine phosphoribosyltransferase, [2-([2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethyl]{2-[(2-oxoethyl)(2-phosphonoethyl)amino]ethyl}amino)ethyl]phosphonic acid, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: 6-oxopurine phosphoribosyltransferase, cytoplasmic, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 90739.57

構造登録者

Eng, W.S.,Hockova, D.,Spacek, P.,West, N.P.,Woods, K.,Naesens, L.M.J.,Keough, D.T.,Guddat, L.W. (登録日: 2014-10-03, 公開日: 2015-05-20, 最終更新日: 2024-02-28)

主引用文献

Eng, W.S.,Hockova, D.,Spacek, P.,Janeba, Z.,West, N.P.,Woods, K.,Naesens, L.M.,Keough, D.T.,Guddat, L.W.
First Crystal Structures of Mycobacterium tuberculosis 6-Oxopurine Phosphoribosyltransferase: Complexes with GMP and Pyrophosphate and with Acyclic Nucleoside Phosphonates Whose Prodrugs Have Antituberculosis Activity.
J.Med.Chem., 58:4822-4838, 2015

PubMed Abstract: Human tuberculosis is a chronic infectious disease affecting millions of lives. Because of emerging resistance to current medications, new therapeutic drugs are needed. One potential new target is hypoxanthine-guanine phosphoribosyltransferase (MtHGPRT), a key enzyme of the purine salvage pathway. Here, newly synthesized acyclic nucleoside phosphonates (ANPs) have been shown to be competitive inhibitors of MtHGPRT with Ki values as low as 0.69 μM. Prodrugs of these compounds arrest the growth of a virulent strain of M. tuberculosis with MIC50 values as low as 4.5 μM and possess low cytotoxicity in mammalian cells (CC50 values as high as >300 μM). In addition, the first crystal structures of MtHGPRT (2.03-2.76 Å resolution) have been determined, three of these in complex with novel ANPs and one with GMP and pyrophosphate. These data provide a solid foundation for the further development of ANPs as selective inhibitors of MtHGPRT and as antituberculosis agents.

PubMed: 25915781
DOI: 10.1021/acs.jmedchem.5b00611

実験手法

X-RAY DIFFRACTION (2.0322 Å)