3p8e

Crystal structure of human DIMETHYLARGININE DIMETHYLAMINOHYDROLASE-1 (DDAH-1) covalently bound with N5-(1-iminopentyl)-L-ornithineCrystal structure of human DIMETHYLARGININE DIMETHYLAMINOHYDROLASE-1 (DDAH-1) covalently bound with N5-(1-iminopentyl)-L-ornithine

Structural highlights 3p8e 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. Ligands: Related: 3i2e, 3i4a, 3p8p Gene: DDAH, DDAH1 (Homo sapiens) Activity: Dimethylargininase, with EC number 3.5.3.18 Resources: FirstGlance, OCA, RCSB, PDBsum 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. Publication Abstract from PubMed C-Alkyl amidine analogues of asymmetric N(omega),N(omega)-dimethyl-L-arginine are dual-targeted inhibitors of both human DDAH-1 and nitric oxide (NO) synthase, and provide a promising scaffold for the development of therapeutics to control NO overproduction in a variety of pathologies including septic shock and some cancers. Using a two-part click-chemistry-mediated activity probe, a homologated series of C-alkyl amidines were ranked for their ability to inhibit DDAH-1 within cultured HEK 293T cells. N(5)-(1-Iminopentyl)-L-ornithine was determined to be the most potent compound in vitro (K(d)=7 muM) as well as in cultured cells, and the binding conformation and covalent reversible mode of inhibition was investigated by comparison of interactions made with DDAH-1 and a catalytically inactive C274S variant, as gauged by X-ray crystallography and isothermal titration calorimetry. By interrupting the ability of the inhibitor to form a covalent bond, the contribution of this interaction could be estimated. These results suggest that further stabilization of the covalent adduct is a promising strategy for lead optimization in the design of effective reagents to block NO synthesis. Characterization of C-Alkyl Amidines as Bioavailable Covalent Reversible Inhibitors of Human DDAH-1.,Lluis M, Wang Y, Monzingo AF, Fast W, Robertus JD ChemMedChem. 2010 Oct 26. PMID:20979083 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 3p8e, resolution 2.49Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image