3GEP

Human hypoxanthine guanine phosphoribosyltranserfase in complex with (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)guanine

3GEP の概要

• エントリーDOI: 10.2210/pdb3gep/pdb
• 関連するPDBエントリー: 1BZY 1D6N 1HMP 1Z7G
• 分子名称: Hypoxanthine-guanine phosphoribosyltransferase, {[(1S)-2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-1-(hydroxymethyl)ethoxy]methyl}phosphonic acid (3 entities in total)
• 機能のキーワード: phosphoribosyltransferase, acyclic nucleoside phosphonate, purine salvage pathway, malarial chemotherapeutic, acetylation, cytoplasm, disease mutation, glycosyltransferase, gout, magnesium, metal-binding, purine salvage, transferase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm: P00492
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 49600.86

構造登録者

Guddat, L.W.,Keough, D.T.,Jersey, J. (登録日: 2009-02-25, 公開日: 2009-08-18, 最終更新日: 2023-11-01)

主引用文献

Keough, D.T.,Hockova, D.,Holy, A.,Naesens, L.M.,Skinner-Adams, T.S.,Jersey, J.,Guddat, L.W.
Inhibition of hypoxanthine-guanine phosphoribosyltransferase by acyclic nucleoside phosphonates: a new class of antimalarial therapeutics.
J.Med.Chem., 52:4391-4399, 2009

PubMed Abstract: The purine salvage enzyme hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) is essential for purine nucleotide and hence nucleic acid synthesis in the malaria parasite, Plasmodium falciparum. Acyclic nucleoside phosphonates (ANPs) are analogues of the nucleotide product of the reaction, comprising a purine base joined by a linker to a phosphonate moiety. K(i) values for 19 ANPs were determined for Pf HGXPRT and the corresponding human enzyme, HGPRT. Values for Pf HGXPRT were as low as 100 nM, with selectivity for the parasite enzyme of up to 58. Structures of human HGPRT in complex with three ANPs are reported. On binding, a large mobile loop in the free enzyme moves to partly cover the active site. For three ANPs, the IC(50) values for Pf grown in cell culture were 1, 14, and 46 microM, while the cytotoxic concentration for the first compound was 489 microM. These results provide a basis for the design of potent and selective ANP inhibitors of Pf HGXPRT as antimalarial drug leads.

PubMed: 19527031
DOI: 10.1021/jm900267n

実験手法

X-RAY DIFFRACTION (2.6 Å)