6xpc | pdb_00006xpc
Structure of human GGT1 in complex with full GSH molecule
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 PubMedOverexpression of gamma-glutamyl transpeptidase(GGT1) has been implicated in an array of humandiseases including asthma, reperfusion injury,and cancer. Inhibitors are needed for therapy, butdevelopment of potent, specific inhibitors ofGGT1 has been hampered by a lack of structuralinformation regarding substrate binding andcleavage. To enhance our understanding of themolecular mechanism of substrate cleavage, wehave solved the crystal structures of humanGGT1 (hGGT1) with glutathione (a substrate)and a phosphate-glutathione analog (anirreversible inhibitor) bound in the active site.These are the first structures of any eukaryoticGGT with the cysteinylglycine region of thesubstrate-binding site occupied. These structuresand the structure of apo-hGGT reveal movementof amino acid residues within the active site as thesubstrate binds. Asn-401 and Thr-381 each formhydrogen bonds with two atoms of GSH spanningthe gamma-glutamyl bond. Three different atoms ofhGGT1 interact with the carboxyl-oxygen of thecysteine of GSH. Interactions between theenzyme and substrate change as the substratemoves deeper into the active site cleft. Thesubstrate reorients and a new hydrogen bond isformed between the substrate and the oxyanionhole. Thr-381 is locked into a singleconformation as an acyl bond forms between thesubstrate and the enzyme. These data provideinsight on a molecular level into the substratespecificity of hGGT1 and provide an explanationfor seemingly disparate observations regardingthe enzymatic activity of hGGT1 mutants. Thisknowledge will aid in the design of clinicallyuseful hGGT1 inhibitors. Crystal structures of glutathione- and inhibitor-bound human GGT1: Critical interactions within the cysteinylglycine binding site.,Terzyan SS, Nguyen LT, Burgett AWG, Heroux A, Smith CA, You Y, Hanigan MH J Biol Chem. 2020 Nov 13. pii: RA120.016265. doi: 10.1074/jbc.RA120.016265. PMID:33187988[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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