1P19

Hypoxanthine Phosphoribosyltransferase from Trypanosoma cruzi, in complex with the product IMP

1P19 の概要

• エントリーDOI: 10.2210/pdb1p19/pdb
• 関連するPDBエントリー: 1p17 1p18 1tc1 1tc2
• 分子名称: hypoxanthine phosphoribosyltransferase, INOSINIC ACID (3 entities in total)
• 機能のキーワード: transferase, glycosyltransferase, phosphoribosyltransferase, nucleotide metabolism, purine salvage, product complex
• 由来する生物種: Trypanosoma cruzi
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 103774.44

構造登録者

Medrano, F.J.,Eakin, A.E.,Craig III, S.P. (登録日: 2003-04-11, 公開日: 2004-05-18, 最終更新日: 2024-02-14)

主引用文献

Canyuk, B.,Medrano, F.J.,Wenck, M.A.,Focia, P.J.,Eakin, A.E.,Craig III, S.P.
Interactions at the dimer interface influence the relative efficiencies for purine nucleotide synthesis and pyrophosphorolysis in a phosphoribosyltransferase.
J.Mol.Biol., 335:905-921, 2004

PubMed Abstract: Enzymes that salvage 6-oxopurines, including hypoxanthine phosphoribosyltransferases (HPRTs), are potential targets for drugs in the treatment of diseases caused by protozoan parasites. For this reason, a number of high-resolution X-ray crystal structures of the HPRTs from protozoa have been reported. Although these structures did not reveal why HPRTs need to form dimers for catalysis, they revealed the existence of potentially relevant interactions involving residues in a loop of amino acid residues adjacent to the dimer interface, but the contributions of these interactions to catalysis remained poorly understood. The loop, referred to as active-site loop I, contains an unusual non-proline cis-peptide and is composed of residues that are structurally analogous with Leu67, Lys68, and Gly69 in the human HPRT. Functional analyses of site-directed mutations (K68D, K68E, K68N, K68P, and K68R) in the HPRT from Trypanosoma cruzi, etiologic agent of Chagas' disease, show that the side-chain at position 68 can differentially influence the K(m) values for all four substrates as well as the k(cat) values for both IMP formation and pyrophosphorolysis. Also, the results for the K68P mutant are inconsistent with a cis-trans peptide isomerization-assisted catalytic mechanism. These data, together with the results of structural studies of the K68R mutant, reveal that the side-chain of residue 68 does not participate directly in reaction chemistry, but it strongly influences the relative efficiencies for IMP formation and pyrophosphorolysis, and the prevalence of lysine at position 68 in the HPRT of the majority of eukaryotes is consistent with there being a biological role for nucleotide pyrophosphorolysis.

PubMed: 14698288
DOI: 10.1016/j.jmb.2003.11.012

実験手法

X-RAY DIFFRACTION (2.3 Å)