1NJJ

Crystal structure determination of T. brucei ornithine decarboxylase bound to D-ornithine and to G418

1NJJ の概要

• エントリーDOI: 10.2210/pdb1njj/pdb
• 関連するPDBエントリー: 1f3t 1QU4
• 分子名称: ornithine decarboxylase, GENETICIN, N~2~-({3-HYDROXY-2-METHYL-5-[(PHOSPHONOOXY)METHYL]PYRIDIN-4-YL}METHYL)-D-ORNITHINE, ... (4 entities in total)
• 機能のキーワード: ornithine decarboxylase, odc, plp, pyridoxal 5'-phosphate, d-ornithine, g418, lyase
• 由来する生物種: Trypanosoma brucei gambiense
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 191545.23

構造登録者

Jackson, L.K.,Goldsmith, E.J.,Phillips, M.A. (登録日: 2002-12-31, 公開日: 2003-08-26, 最終更新日: 2023-08-16)

主引用文献

Jackson, L.K.,Goldsmith, E.J.,Phillips, M.A.
X-ray Structure Determination of Trypanosoma brucei Ornithine Decarboxylase Bound to D-Ornithine and to G418: INSIGHTS INTO SUBSTRATE BINDING AND ODC CONFORMATIONAL FLEXIBILITY.
J.Biol.Chem., 278:22037-22043, 2003

PubMed Abstract: Ornithine decarboxylase (ODC) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the rate-determining step in the biosynthesis of polyamines. ODC is a proven drug target to treat African sleeping sickness. The x-ray crystal structure of Trypanosoma brucei ODC in complex with d-ornithine (d-Orn), a substrate analog, and G418 (Geneticin), a weak non-competitive inhibitor, was determined to 2.5-A resolution. d-Orn forms a Schiff base with PLP, and the side chain is in a similar position to that observed for putrescine and alpha-difluoromethylornithine in previous T. brucei ODC structures. The d-Orn carboxylate is positioned on the solvent-exposed side of the active site (si face of PLP), and Gly-199, Gly-362, and His-197 are the only residues within 4.2 A of this moiety. This structure confirms predictions that the carboxylate of d-Orn binds on the si face of PLP, and it supports a model in which the carboxyl group of the substrate l-Orn would be buried on the re face of the cofactor in a pocket that includes Phe-397, Tyr-389, Lys-69 (methylene carbons), and Asp-361. Electron density for G418 was observed at the boundary between the two domains within each ODC monomer. A ten-amino acid loop region (392-401) near the 2-fold axis of the dimer interface, which contributes several residues that form the active site, is disordered in this structure. The disordering of residues in the active site provides a potential mechanism for inhibition by G418 and suggests that allosteric inhibition from this site is feasible.

PubMed: 12672797
DOI: 10.1074/jbc.M300188200

実験手法

X-RAY DIFFRACTION (2.45 Å)