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J. Biol. Chem., Vol. 277, Issue 27, 24522-24529, July 5, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/27/24522    most recent M202020200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, H. Articles by Van Roey, P. Search for Related Content PubMed PubMed Citation Articles by Li, H. Articles by Van Roey, P. Social Bookmarking                      What's this?

Three-dimensional Structure of Human -Glutamyl Hydrolase
A CLASS I GLUTAMINE AMIDOTRANSFERASE ADAPTED FOR A COMPLEX SUBSTRATE^*

Hongmin Li, Thomas J. Ryan, Karen J. Chave, and Patrick Van Roey

From the Division of Molecular Medicine, Wadsworth Center, Albany, New York 12201-0509

-Glutamyl hydrolase catalyzes the cleavage of the -glutamyl chain of folylpoly--glutamyl substrates and is a central enzyme in folyl and antifolyl poly--glutamate metabolism. The crystal structure of human -glutamyl hydrolase, determined at 1.6-Å resolution, reveals that the protein is a homodimer. The overall structure of human -glutamyl hydrolase contains 11 -helices and 14 -strands, with a fold in which a central eight-stranded -sheet is sandwiched by three and five -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 -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.

The atomic coordinates and the structure factors (code 1L9X) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

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