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From Proteopedia
Crystal Structure of human GGT1 in complex with GGsTop inhibitor
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 PubMedGamma-glutamyl transpeptidase 1 (GGT1) is a cell surface, N-terminal nucleophile hydrolase that cleaves glutathione and other gamma-glutamyl compounds. GGT1 expression is essential in cysteine homeostasis and its induction has been implicated in the pathology of asthma, reperfusion injury and cancer. In this study, we report four new crystal structures of human GGT1 (hGGT1) which show conformational changes within the active site as the enzyme progresses from the free enzyme to inhibitor-bound tetrahedral transition states and finally to the glutamate-bound structure prior to the release of this final product of the reaction. The structure of the apo-enzyme shows flexibility within the active site. The serine-borate-bound hGGT1 crystal structure demonstrates that serine-borate occupies the active site of enzyme resulting in an enzyme-inhibitor complex that replicates the enzymes tetrahedral intermediate/transition state. The structure of GGsTop-bound hGGT1 reveals its interactions with the enzyme and why neutral phosphonate diesters are more potent inhibitors than mono-anionic phosphonates. These structures are the first structures for any eukaryotic GGT that include a molecule in the active site covalently bound to the catalytic Thr381. The glutamate-bound structure shows the conformation of the enzyme prior to release of the final product and revealed novel information regarding the displacement of the main chain atoms that form the oxyanion hole and movement of the lid loop region when the active site is occupied. These data provide new insights into the mechanism of hGGT1-catalyzed reactions and will be invaluable in the development of new classes of hGGT1 inhibitors for therapeutic use. Human Gamma-Glutamyl Transpeptidase 1: Structures of the Free Enzyme, Inhibitor-Bound Tetrahedral Transition States and Glutamate-Bound Enzyme Reveal Novel Movement within the Active Site during Catalysis.,Terzyan SS, Burgett AW, Heroux A, Smith CA, Mooers BH, Hanigan MH J Biol Chem. 2015 May 26. pii: jbc.M115.659680. PMID:26013825[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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