6D24

Trypanosoma cruzi Glucose-6-P Dehydrogenase in complex with G6P

「4EM5」から置き換えられました

6D24 の概要

• エントリーDOI: 10.2210/pdb6d24/pdb
• 分子名称: Glucose-6-phosphate 1-dehydrogenase, 6-O-phosphono-beta-D-glucopyranose, SULFATE ION, ... (7 entities in total)
• 機能のキーワード: dehydrogenase, pentose phosphate pathway, alpha beta, nad(p) rossmann-like domain, oxidoreductase
• 由来する生物種: Trypanosoma cruzi; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 248619.52

構造登録者

Botti, H.,Ortiz, C.,Comini, M.A.,Larrieux, N.,Buschiazzo, A. (登録日: 2018-04-12, 公開日: 2018-05-02, 最終更新日: 2024-10-16)

主引用文献

Ortiz, C.,Botti, H.,Buschiazzo, A.,Comini, M.A.
Glucose-6-Phosphate Dehydrogenase from the Human Pathogen Trypanosoma cruzi Evolved Unique Structural Features to Support Efficient Product Formation.
J.Mol.Biol., 431:2143-2162, 2019

PubMed Abstract: Glucose-6-phosphate dehydrogenase (G6PDH) is the key enzyme supplying reducing power (NADPH) to the cells, by oxidation of glucose-6-phosphate (G6P), and in the process providing a precursor of ribose-5-phosphate. G6PDH is also a virulence factor of pathogenic trypanosomatid parasites. To uncover the biochemical and structural features that distinguish TcG6PDH from its human homolog, we have solved and analyzed the crystal structures of the G6PDH from Trypanosoma cruzi (TcG6PDH), alone and in complex with G6P. TcG6PDH crystallized as a tetramer and enzymatic assays further indicated that the tetramer is the active form in the parasite, in contrast to human G6PDH, which displays higher activity as a dimer. This quaternary structure was shown to be particularly stable. The molecular reasons behind this disparity were unveiled by structural analyses: a TcG6PDH-specific residue, R323, is located at the dimer-dimer interface, critically contributing with two salt bridges per subunit that are absent in the human enzyme. This explains why TcG6PDH dimerization impaired enzyme activity. The parasite protein is also distinct in displaying a 37-amino-acid extension at the N-terminus, which comprises the non-conserved C8 and C34 involved in the covalent linkage of two neighboring protomers. In addition, a cysteine triad (C53, C94 and C135) specific of Kinetoplastid G6PDHs proved critical for stabilization of TcG6PDH active site. Based on the structural and biochemical data, we posit that the N-terminal region and the catalytic site are highly dynamic. The unique structural features of TcG6PDH pave the way toward the design of efficacious and highly specific anti-trypanosomal drugs.

PubMed: 30930048
DOI: 10.1016/j.jmb.2019.03.023

実験手法

X-RAY DIFFRACTION (3.35 Å)