7s3g

Structure of cofactor pyridoxal 5-phosphate bound human ornithine decarboxylase in complex with citrate at the catalytic center

spinqualitylabelsall models 7s3g, resolution 1.66Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7s3g is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.66Å Ligands: CIT, PLP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DCOR_HUMAN Publication Abstract from PubMed Ornithine decarboxylase (ODC) is the rate-limiting enzyme for the synthesis of polyamines (PAs). PAs are oncometabolites that are required for proliferation, and pharmaceutical ODC inhibition is pursued for the treatment of hyperproliferative diseases, including cancer and infectious diseases. The most potent ODC inhibitor is 1-amino-oxy-3-aminopropane (APA). A previous crystal structure of an ODC-APA complex indicated that APA non-covalently binds ODC and its cofactor pyridoxal 5-phosphate (PLP) and functions by competing with the ODC substrate ornithine for binding to the catalytic site. We have revisited the mechanism of APA binding and ODC inhibition through a new crystal structure of APA-bound ODC, which we solved at 2.49 A resolution. The structure unambiguously shows the presence of a covalent oxime between APA and PLP in the catalytic site, which we confirmed in solution by mass spectrometry. The stable oxime makes extensive interactions with ODC but cannot be catabolized, explaining APA's high potency in ODC inhibition. In addition, we solved an ODC/PLP complex structure with citrate bound at the substrate-binding pocket. These two structures provide new structural scaffolds for developing more efficient pharmaceutical ODC inhibitors. Structural basis of binding and inhibition of ornithine decarboxylase by 1-amino-oxy-3-aminopropane.,Zhou XE, Suino-Powell K, Schultz CR, Aleiwi B, Brunzelle JS, Lamp J, Vega IE, Ellsworth E, Bachmann AS, Melcher K Biochem J. 2021 Dec 10;478(23):4137-4149. doi: 10.1042/BCJ20210647. PMID:34796899 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ornithine decarboxylase

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