1L9X

Structure of gamma-Glutamyl Hydrolase

Summary for 1L9X

• Entry DOI: 10.2210/pdb1l9x/pdb
• Descriptor: gamma-glutamyl hydrolase, BETA-MERCAPTOETHANOL (3 entities in total)
• Functional Keywords: gamma-glutamyl hydrolase, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Secreted, extracellular space: Q92820
• Total number of polymer chains: 4
• Total formula weight: 144424.64

Authors

Li, H.,Ryan, T.J.,Chave, K.J.,Van Roey, P. (deposition date: 2002-03-26, release date: 2002-04-10, Last modification date: 2021-04-07)

Primary citation

Li, H.,Ryan, T.J.,Chave, K.J.,Van Roey, P.
Three-dimensional structure of human gamma -glutamyl hydrolase. A class I glatamine amidotransferase adapted for a complex substate.
J.Biol.Chem., 277:24522-24529, 2002

PubMed Abstract: gamma-Glutamyl hydrolase catalyzes the cleavage of the gamma-glutamyl chain of folylpoly-gamma-glutamyl substrates and is a central enzyme in folyl and antifolyl poly-gamma-glutamate metabolism. The crystal structure of human gamma-glutamyl hydrolase, determined at 1.6-A resolution, reveals that the protein is a homodimer. The overall structure of human gamma-glutamyl hydrolase contains 11 alpha-helices and 14 beta-strands, with a fold in which a central eight-stranded beta-sheet is sandwiched by three and five alpha-helices on each side. The topology is very similar to that of the class I glutamine amidotransferase domains, with the only major differences consisting of extensions in four loops and at the C terminus. These insertions are important for defining the substrate binding cleft and/or the dimer interface. Two sequence motifs are found in common between human gamma-glutamyl hydrolase and the class I glutamine amidotransferase family and include the catalytically essential residues, Cys-110 and His-220. These residues are located in the center of a large l-shaped cleft that is closed at one end and open at the other. Several conserved residues, including Glu-114, His-171, Gln-218, and Lys-223, may be important for substrate binding. Modeling of a methotrexate thioester intermediate, based on the corresponding complex of the glutamate thioester intermediate of Escherichia coli carbamoyl-phosphate synthetase, indicates that the substrate binds in an orientation with the pteroyl group toward the open end of the cleft.

PubMed: 11953431
DOI: 10.1074/jbc.M202020200

Experimental method

X-RAY DIFFRACTION (1.6 Å)