5JSQ

Trypanosome brucei Hypoxanthine-guanine phosphoribosyltranferase in complex with a 9-[7-(phosphonoheptyl]guanine

5JSQ の概要

• エントリーDOI: 10.2210/pdb5jsq/pdb
• 関連するPDBエントリー: 5JV5 5K51 5KAM 5KAP
• 分子名称: hypoxanthine-guanine phosphoribosyltranferase, [6-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)hexyl]phosphonic acid, DI(HYDROXYETHYL)ETHER, ... (7 entities in total)
• 機能のキーワード: inhibitor, complex, dimer, enzyme, transferase
• 由来する生物種: Trypanosoma brucei brucei
• 細胞内の位置: Cytoplasm: Q07010
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 49803.34

構造登録者

Teran, D.,Guddat, L. (登録日: 2016-05-09, 公開日: 2016-11-09, 最終更新日: 2023-09-27)

主引用文献

Teran, D.,Hockova, D.,Cesnek, M.,Zikova, A.,Naesens, L.,Keough, D.T.,Guddat, L.W.
Crystal structures and inhibition of Trypanosoma brucei hypoxanthine-guanine phosphoribosyltransferase.
Sci Rep, 6:35894-35894, 2016

PubMed Abstract: Human African Trypanosomiasis (HAT) is a life-threatening infectious disease caused by the protozoan parasite, Trypanosoma brucei (Tbr). Due to the debilitating side effects of the current therapeutics and the emergence of resistance to these drugs, new medications for this disease need to be developed. One potential new drug target is 6-oxopurine phosphoribosyltransferase (PRT), an enzyme central to the purine salvage pathway and whose activity is critical for the production of the nucleotides (GMP and IMP) required for DNA/RNA synthesis within this protozoan parasite. Here, the first crystal structures of this enzyme have been determined, these in complex with GMP and IMP and with three acyclic nucleoside phosphonate (ANP) inhibitors. The K values for GMP and IMP are 30.5 μM and 77 μM, respectively. Two of the ANPs have K values considerably lower than for the nucleotides, 2.3 μM (with guanine as base) and 15.8 μM (with hypoxanthine as base). The crystal structures show that when two of the ANPs bind, they induce an unusual conformation change to the loop where the reaction product, pyrophosphate, is expected to bind. This and other structural differences between the Tbr and human enzymes suggest selective inhibitors for the Tbr enzyme can be designed.

PubMed: 27786284
DOI: 10.1038/srep35894

実験手法

X-RAY DIFFRACTION (1.503 Å)