4GDX

Crystal Structure of Human Gamma-Glutamyl Transpeptidase--Glutamate complex

4GDX の概要

• エントリーDOI: 10.2210/pdb4gdx/pdb
• 関連するPDBエントリー: 2DBU 2DBW 2DBX 2DG5 2EOW 2EOX 2EOY 2NQO 4GG2 4GG3
• 分子名称: Gamma-glutamyltranspeptidase 1 heavy chain, Gamma-glutamyltranspeptidase 1 light chain, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• 機能のキーワード: product-enzyme complex, ntn-hydrolase family, glycoprotein, n-glycosylation, cell surface, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Membrane; Single-pass type II membrane protein: P19440 P19440
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 63000.18

構造登録者

West, M.B.,Chen, Y.,Wickham, S.,Heroux, A.,Cahill, K.,Hanigan, M.H.,Mooers, B.H.M. (登録日: 2012-08-01, 公開日: 2013-09-25, 最終更新日: 2024-11-20)

主引用文献

West, M.B.,Chen, Y.,Wickham, S.,Heroux, A.,Cahill, K.,Hanigan, M.H.,Mooers, B.H.
Novel Insights into Eukaryotic gamma-Glutamyltranspeptidase 1 from the Crystal Structure of the Glutamate-bound Human Enzyme.
J.Biol.Chem., 288:31902-31913, 2013

PubMed Abstract: The enzyme γ-glutamyltranspeptidase 1 (GGT1) is a conserved member of the N-terminal nucleophile hydrolase family that cleaves the γ-glutamyl bond of glutathione and other γ-glutamyl compounds. In animals, GGT1 is expressed on the surface of the cell and has critical roles in maintaining cysteine levels in the body and regulating intracellular redox status. Expression of GGT1 has been implicated as a potentiator of asthma, cardiovascular disease, and cancer. The rational design of effective inhibitors of human GGT1 (hGGT1) has been delayed by the lack of a reliable structural model. The available crystal structures of several bacterial GGTs have been of limited use due to differences in the catalytic behavior of bacterial and mammalian GGTs. We report the high resolution (1.67 Å) crystal structure of glutamate-bound hGGT1, the first of any eukaryotic GGT. Comparisons of the active site architecture of hGGT1 with those of its bacterial orthologs highlight key differences in the residues responsible for substrate binding, including a bimodal switch in the orientation of the catalytic nucleophile (Thr-381) that is unique to the human enzyme. Compared with several bacterial counterparts, the lid loop in the crystal structure of hGGT1 adopts an open conformation that allows greater access to the active site. The hGGT1 structure also revealed tightly bound chlorides near the catalytic residue that may contribute to catalytic activity. These are absent in the bacterial GGTs. These differences between bacterial and mammalian GGTs and the new structural data will accelerate the development of new therapies for GGT1-dependent diseases.

PubMed: 24047895
DOI: 10.1074/jbc.M113.498139

実験手法

X-RAY DIFFRACTION (1.67 Å)