4l8w

Crystal structure of gamma glutamyl hydrolase (H218N) from zebrafish complex with MTX polyglutamate

spinqualitylabelsall models 4l8w, resolution 2.39Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4l8w is a 6 chain structure with sequence from Danio rerio. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.39Å Ligands: DGL, MTX Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q6NY42_DANRE Publication Abstract from PubMed gamma-Glutamyl hydrolases (gammaGH) catalyze the hydrolysis of gamma-linked glutamate residues from the polyglutamyl of folates and antifolates, such as methotrexate (MTX), a widely used anticancer drug. We describe the first crystal structures of the endopeptidase-type gammaGH (zgammaGH) from zebrafish and the mutant complexes with MTX(Glu)5 and hydrolyzed MTX(Glu)1, revealing the complete set of key residues involved in hydrolysis as well as the substrate-binding subsites (-1 to +2). The side chain of Phe20 and the 6-methylpterin ring of MTX(Glu)5 invoke pi-pi interactions to promote distinct concerted conformational alterations involving approximately 90 degrees rotations in the complexes with the zgammaGH-C108A and zgammaGH-H218N mutant proteins. The structural geometries of the MTX(Glu)5 and hydrolyzed MTX(Glu)1 in the mutant complexes differ significantly from those of the previously known MTX(Glu)1, providing polymorphic information. Together with the structural comparison and the activity analysis, these results shed light on the catalytic mechanism and substrate recognition of zgammaGH and other gamma-glutamyl hydrolases. Structural insights into the hydrolysis and polymorphism of methotrexate polyglutamate by zebrafish gamma-glutamyl hydrolase.,Chuankhayan P, Kao TT, Lin CC, Guan HH, Nakagawa A, Fu TF, Chen CJ J Med Chem. 2013 Oct 10;56(19):7625-35. doi: 10.1021/jm401013e. Epub 2013 Sep 27. PMID:24028568 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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