4JIT

Crystal Structure of E. coli XGPRT in complex with (S)-3-(Guanin-9-yl)pyrrolidin-N-ylacetylphosphonic acid

4JIT の概要

• エントリーDOI: 10.2210/pdb4jit/pdb
• 関連するPDBエントリー: 4JLS
• 分子名称: Xanthine phosphoribosyltransferase, {2-[(3S)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)pyrrolidin-1-yl]-2-oxoethyl}phosphonic acid (3 entities in total)
• 機能のキーワード: xanthine-guanine phosphoribosyltransferase, purine salvage, nucleoside phosphonate, antibacterial, transferase
• 由来する生物種: Escherichia coli
• 細胞内の位置: Cell membrane ; Peripheral membrane protein : H0Q6L9
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 68650.77

構造登録者

Keough, D.T.,Hockova, D.,Rejman, D.,Spacek, P.,Vrbkova, S.,Krecmerova, M.,Eng, W.S.,Jans, H.,West, N.P.,Naesens, L.M.J.,de Jersey, J.,Guddat, L.W. (登録日: 2013-03-07, 公開日: 2014-12-24, 最終更新日: 2024-02-28)

主引用文献

Keough, D.T.,Hockova, D.,Rejman, D.,Spacek, P.,Vrbkova, S.,Krecmerova, M.,Eng, W.S.,Jans, H.,West, N.P.,Naesens, L.M.,de Jersey, J.,Guddat, L.W.
Inhibition of the Escherichia coli 6-oxopurine phosphoribosyltransferases by nucleoside phosphonates: potential for new antibacterial agents.
J.Med.Chem., 56:6967-6984, 2013

PubMed Abstract: Escherichia coli (Ec) cells possess two purine salvage enzymes: xanthine-guanine phosphoribosyltransferase (XGPRT) and hypoxanthine phosphoribosyltransferase (HPRT). EcXGPRT shares a common structural feature with other members of this family, a flexible loop that closes over the active site during catalysis. The replacement of six of these amino acids by alanine has no effect on the Km for the two substrates. However, the Ki for the nucleoside monophosphate increases by 27-fold, and the kcat is reduced by ∼200-fold. Nucleoside phosphonates (NP) are good inhibitors of EcXGPRT and EcHPRT, with Ki values as low as 10 nM. In the absence of the flexible loop, these values increase by 5- to 30-fold, indicating the importance of the loop for high-affinity inhibition. Crystal structures of two NPs in complex with EcXGPRT explain the tight binding. Prodrugs of NPs with low Ki values for EcXGPRT or EcHPRT exhibit IC50 values between 5 and 23 μM against Mycobacterium tuberculosis in cell-based assays, suggesting that these compounds are therapeutic leads against pathogenic bacteria.

PubMed: 23927482
DOI: 10.1021/jm400779n

実験手法

X-RAY DIFFRACTION (2.8 Å)