4IJQ

Human hypoxanthine-guanine phosphoribosyltransferase in complex with [(2-((Guanine-9H-yl)methyl)propane-1,3-diyl)bis(oxy)]bis(methylene))diphosphonic acid

4IJQ の概要

• エントリーDOI: 10.2210/pdb4ijq/pdb
• 関連するPDBエントリー: 1BZY 1CJB 1HMP 3GEP
• 分子名称: Hypoxanthine-guanine phosphoribosyltransferase, [{2-[(guanine-9-yl)methyl]propane-1,3-diyl}bis(oxymethylene)]bis(phosphonic acid), SULFATE ION, ... (5 entities in total)
• 機能のキーワード: gmp, 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: 4
• 化学式量合計: 103528.08

構造登録者

Guddat, L.W.,Keough, D.T.,Hockova, D. (登録日: 2012-12-22, 公開日: 2013-03-27, 最終更新日: 2024-03-20)

主引用文献

Keough, D.T.,Spacek, P.,Hockova, D.,Tichy, T.,Vrbkova, S.,Slavetinska, L.,Janeba, Z.,Naesens, L.,Edstein, M.D.,Chavchich, M.,Wang, T.H.,Jersey, J.,Guddat, L.W.
Acyclic nucleoside phosphonates containing a second phosphonate group are potent inhibitors of 6-oxopurine phosphoribosyltransferases and have antimalarial activity
J.Med.Chem., 56:2513-2526, 2013

PubMed Abstract: Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) 6-oxopurine phosphoribosyltransferases (PRTs). Chemical modifications based on the crystal structure of 2-(phosphonoethoxy)ethylguanine (PEEG) in complex with human HGPRT have led to the design of new ANPs. These novel compounds contain a second phosphonate group attached to the ANP scaffold. {[(2-[(Guanine-9H-yl)methyl]propane-1,3-diyl)bis(oxy)]bis(methylene)}diphosphonic acid (compound 17) exhibited a Ki value of 30 nM for human HGPRT and 70 nM for Pf HGXPRT. The crystal structure of this compound in complex with human HGPRT shows that it fills or partially fills three critical locations in the active site: the binding sites of the purine base, the 5'-phosphate group, and pyrophosphate. This is the first HG(X)PRT inhibitor that has been able to achieve this result. Prodrugs have been synthesized resulting in IC50 values as low as 3.8 μM for Pf grown in cell culture, up to 25-fold lower compared to the parent compounds.

PubMed: 23448281
DOI: 10.1021/jm301893b

実験手法

X-RAY DIFFRACTION (2.004 Å)