4o7d

Crystal structure of human glutaminase in complex DON

spinqualitylabelsall models 4o7d, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4o7d is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ONL Gene: GLS, GLS1, KIAA0838 (HUMAN) Activity: Glutaminase, with EC number 3.5.1.2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [GLSK_HUMAN] Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine. Plays a role in maintaining acid-base homeostasis. Regulates the levels of the neurotransmitter glutamate in the brain. Isoform 2 lacks catalytic activity. Publication Abstract from PubMed Glutaminase is a metabolic enzyme responsible for glutaminolysis, a process harnessed by cancer cells to feed their accelerated growth and proliferation. Among the glutaminase isoforms, human kidney-type glutaminase (KGA) is often upregulated in cancer and is thus touted as an attractive drug target. Here we report the active site inhibition mechanism of KGA through the crystal structure of the catalytic domain of KGA (cKGA) in complex with 6-diazo-5-oxo-L-norleucine (DON), a substrate analogue of glutamine. DON covalently binds with the active site Ser286 and interacts with residues such as Tyr249, Asn335, Glu381, Asn388, Tyr414, Tyr466 and Val484. The nucleophilic attack of Ser286 sidechain on DON releases the diazo group (N2) from the inhibitor and results in the formation of an enzyme-inhibitor complex. Mutational studies confirmed the key role of these residues in the activity of KGA. This study will be important in the development of KGA active site inhibitors for therapeutic interventions. Structural basis for the active site inhibition mechanism of human kidney-type glutaminase (KGA).,Thangavelu K, Chong QY, Low BC, Sivaraman J Sci Rep. 2014 Jan 23;4:3827. doi: 10.1038/srep03827. PMID:24451979 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Glutaminase

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