6BO7

Crystal structure of Plasmodium vivax hypoxanthine guanine phosphoribosyltransferase in complex with [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine

Replaces:  5HHU

Summary for 6BO7

• Entry DOI: 10.2210/pdb6bo7/pdb
• Descriptor: Hypoxanthine phosphoribosyltransferase, MAGNESIUM ION, [3-[(3~{R},4~{R})-3-(2-azanyl-6-oxidanylidene-1~{H}-purin-9-yl)-4-[(2~{S})-2-oxidanyl-2-phosphono-ethoxy]pyrrolidin-1-y l]-3-oxidanylidene-propyl]phosphonic acid (3 entities in total)
• Functional Keywords: inhibitor, complex, phosphonate, phosphoribosyltransferase, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Plasmodium vivax (malaria parasite P. vivax)
• Total number of polymer chains: 12
• Total formula weight: 339094.01

Authors

Guddat, L.W.,Keough, D.T.,Rejman, D. (deposition date: 2017-11-18, release date: 2017-12-13, Last modification date: 2024-03-13)

Primary citation

Keough, D.T.,Rejman, D.,Pohl, R.,Zbornikova, E.,Hockova, D.,Croll, T.,Edstein, M.D.,Birrell, G.W.,Chavchich, M.,Naesens, L.M.J.,Pierens, G.K.,Brereton, I.M.,Guddat, L.W.
Design of Plasmodium vivax Hypoxanthine-Guanine Phosphoribosyltransferase Inhibitors as Potential Antimalarial Therapeutics.
ACS Chem. Biol., 13:82-90, 2018

PubMed Abstract: Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) are the foremost causative agents of malaria. Due to the development of resistance to current antimalarial medications, new drugs for this parasitic disease need to be discovered. The activity of hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase, HG[X]PRT, is reported to be essential for the growth of both of these parasites, making it an excellent target for antimalarial drug discovery. Here, we have used rational structure-based methods to design an inhibitor, [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine, of PvHGPRT and PfHGXPRT that has K values of 8 and 7 nM, respectively, for these two enzymes. The crystal structure of PvHGPRT in complex with this compound has been determined to 2.85 Å resolution. The corresponding complex with human HGPRT was also obtained to allow a direct comparison of the binding modes of this compound with the two enzymes. The tetra-(ethyl l-phenylalanine) tetraamide prodrug of this compound was synthesized, and it has an IC of 11.7 ± 3.2 μM against Pf lines grown in culture and a CC in human A549 cell lines of 102 ± 11 μM, thus giving it a ∼10-fold selectivity index.

PubMed: 29161011
DOI: 10.1021/acschembio.7b00916

Experimental method

X-RAY DIFFRACTION (2.856 Å)