7LD9

Structure of human GGT1 in complex with ABBA

Summary for 7LD9

• Entry DOI: 10.2210/pdb7ld9/pdb
• Descriptor: Glutathione hydrolase 1 heavy chain, Glutathione hydrolase 1 light chain, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: substrate-enzyme complex, ntn-hydrolase family, glycoprotein, n-glycosylation, cell surface, hydrolase-hydrolase inhibitor complex, abba, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 60978.03

Authors

Terzyan, S.S.,Hanigan, M. (deposition date: 2021-01-12, release date: 2022-02-23, Last modification date: 2024-11-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.42 Å)