4gg2 | pdb_00004gg2
The crystal structure of glutamate-bound human gamma-glutamyltranspeptidase 1
Structural highlights
DiseaseGGT1_HUMAN Gamma-glutamyl transpeptidase deficiency. The disease is caused by mutations affecting the gene represented in this entry. FunctionGGT1_HUMAN Initiates extracellular glutathione (GSH) breakdown, provides cells with a local cysteine supply and contributes to maintain intracellular GSH level. It is part of the cell antioxidant defense mechanism. Catalyzes the transfer of the glutamyl moiety of glutathione to amino acids and dipeptide acceptors. Alternatively, glutathione can be hydrolyzed to give Cys-Gly and gamma glutamate. Isoform 3 seems to be inactive.[1] [2] Publication Abstract from PubMedThe enzyme gamma-glutamyl transpeptidase 1 (GGT1) is a conserved member of the Nterminal nucleophile (Ntn)-hydroylase family that cleaves the gamma-glutamyl bond of glutathione and other gamma-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 A) crystal structure of glutamate-bound hGGT1, the first of any eukaryotic GGT. Comparisons of the active site architecture of hGGT1 to 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 to 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. Novel insights into eukaryotic gamma-glutamyl transpeptidase 1 from the crystal structure of the glutamate-bound human enzyme.,West MB, Chen Y, Wickham S, Heroux A, Cahill K, Hanigan MH, Mooers BH J Biol Chem. 2013 Sep 18. PMID:24047895[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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