3i2e | pdb_00003i2e

Crystal structure of human dimethylarginine dymethylaminohydrolase-1 (DDAH-1)

spinqualitylabelsall models 3i2e, resolution 2.03Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3i2e 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 2.03Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function DDAH1_HUMAN Hydrolyzes N(G),N(G)-dimethyl-L-arginine (ADMA) and N(G)-monomethyl-L-arginine (MMA) which act as inhibitors of NOS. Has therefore a role in the regulation of nitric oxide generation. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Molecules that block nitric oxide's (NO) biosynthesis are of significant interest. For example, nitric oxide synthase (NOS) inhibitors have been suggested as antitumor therapeutics, as have inhibitors of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that catabolizes endogenous NOS inhibitors. Dual-targeted inhibitors hold promise as more effective reagents to block NO biosynthesis than single-targeted compounds. In this study, a small set of known NOS inhibitors are surveyed as inhibitors of recombinant human DDAH-1. From these, an alkylamidine scaffold is selected for homologation. Stepwise lengthening of one substituent converts an NOS-selective inhibitor into a dual-targeted NOS/DDAH-1 inhibitor and then into a DDAH-1 selective inhibitor, as seen in the inhibition constants of N(5)-(1-iminoethyl)-, N(5)-(1-iminopropyl)-, N(5)-(1-iminopentyl)- and N(5)-(1-iminohexyl)-l-ornithine for neuronal NOS (1.7, 3, 20, >1,900 muM, respectively) and DDAH-1 (990, 52, 7.5, 110 muM, respectively). A 1.9 A X-ray crystal structure of the N(5)-(1-iminopropyl)-l-ornithine:DDAH-1 complex indicates covalent bond formation between the inhibitor's amidino carbon and the active-site Cys274, and solution studies show reversible competitive inhibition, consistent with a reversible covalent mode of DDAH inhibition by alkylamidine inhibitors. These represent a versatile scaffold for the development of a targeted polypharmacological approach to control NO biosynthesis. Developing Dual and Specific Inhibitors of Dimethylarginine Dimethylaminohydrolase-1 and Nitric Oxide Synthase: Toward a Targeted Polypharmacology To Control Nitric Oxide.,Wang Y, Monzingo AF, Hu S, Schaller TH, Robertus JD, Fast W Biochemistry. 2009 Aug 19. PMID:19663506 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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