7LD9

Structure of human GGT1 in complex with ABBA

7LD9 の概要

• エントリーDOI: 10.2210/pdb7ld9/pdb
• 分子名称: Glutathione hydrolase 1 heavy chain, Glutathione hydrolase 1 light chain, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• 機能のキーワード: substrate-enzyme complex, ntn-hydrolase family, glycoprotein, n-glycosylation, cell surface, hydrolase-hydrolase inhibitor complex, abba, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 60978.03

構造登録者

Terzyan, S.S.,Hanigan, M. (登録日: 2021-01-12, 公開日: 2022-02-23, 最終更新日: 2024-11-06)

主引用文献

Nguyen, L.,Schultz, D.C.,Terzyan, S.S.,Rezaei, M.,Songb, J.,Li, C.,You, Y.,Hanigan, M.H.
Design and evaluation of novel analogs of 2-amino-4-boronobutanoic acid (ABBA) as inhibitors of human gamma-glutamyl transpeptidase.
Bioorg.Med.Chem., 73:116986-116986, 2022

PubMed Abstract: Inhibitors of gamma-glutamyl transpeptidase (GGT1, aka gamma-glutamyl transferase) are needed for the treatment of cancer, cardiovascular illness and other diseases. Compounds that inhibit GGT1 have been evaluated in the clinic, but no inhibitor has successfully demonstrated specific and systemic GGT1 inhibition. All have severe side effects. L-2-amino-4‑boronobutanoic acid (l-ABBA), a glutamate analog, is the most potent GGT1 inhibitor in vitro. In this study, we have solved the crystal structure of human GGT1 (hGGT1) with ABBA bound in the active site. The structure was interrogated to identify interactions between the enzyme and the inhibitor. Based on these data, a series of novel ABBA analogs were designed and synthesized. Their inhibitory activity against the hydrolysis and transpeptidation activities of hGGT1 were determined. The lead compounds were crystalized with hGGT1 and the structures solved. The kinetic data and structures of the complexes provide new insights into the critical role of protein structure dynamics in developing compounds for inhibition of hGGT1.

PubMed: 36208545
DOI: 10.1016/j.bmc.2022.116986

実験手法

X-RAY DIFFRACTION (1.42 Å)