4L95

Crystal structure of gamma glutamyl hydrolase (H218N) from zebrafish

4L95 の概要

• エントリーDOI: 10.2210/pdb4l95/pdb
• 関連するPDBエントリー: 4L7Q 4L8F 4L8W 4L8Y
• 分子名称: Gamma-glutamyl hydrolase, GLYCEROL (3 entities in total)
• 機能のキーワード: sandwiched-like domain, hydrolase
• 由来する生物種: Danio rerio (zebra fish)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 212633.79

構造登録者

Chuankhayan, P.,Kao, T.-T.,Chen, C.-J.,Fu, T.-F. (登録日: 2013-06-18, 公開日: 2014-05-14, 最終更新日: 2023-11-08)

主引用文献

Chuankhayan, P.,Kao, T.-T.,Lin, C.-C.,Guan, H.-H.,Nakagawa, A.,Fu, T.-F.,Chen, C.-J.
Structural insights into the hydrolysis and polymorphism of methotrexate polyglutamate by zebrafish gamma-glutamyl hydrolase
J.Med.Chem., 56:7625-7635, 2013

PubMed Abstract: γ-Glutamyl hydrolases (γGH) catalyze the hydrolysis of γ-linked glutamate residues from the polyglutamyl of folates and antifolates, such as methotrexate (MTX), a widely used anticancer drug. We describe the first crystal structures of the endopeptidase-type γGH (zγGH) from zebrafish and the mutant complexes with MTX(Glu)5 and hydrolyzed MTX(Glu)1, revealing the complete set of key residues involved in hydrolysis as well as the substrate-binding subsites (-1 to +2). The side chain of Phe20 and the 6-methylpterin ring of MTX(Glu)5 invoke π-π interactions to promote distinct concerted conformational alterations involving ∼90° rotations in the complexes with the zγGH-C108A and zγGH-H218N mutant proteins. The structural geometries of the MTX(Glu)5 and hydrolyzed MTX(Glu)1 in the mutant complexes differ significantly from those of the previously known MTX(Glu)1, providing polymorphic information. Together with the structural comparison and the activity analysis, these results shed light on the catalytic mechanism and substrate recognition of zγGH and other γ-glutamyl hydrolases.

PubMed: 24028568
DOI: 10.1021/jm401013e

実験手法

X-RAY DIFFRACTION (2.34 Å)