3P8P: Crystal Structure of Human Dimethylarginine Dimethylaminohydrolase-1 (DDAH-1) variant C274S bound with N5-(1-iminopentyl)-L-ornithine

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.
PDB ID: 3P8PDownload
MMDB ID: 86153
PDB Deposition Date: 2010/10/14
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 2.5  Å
Source Organism:
Similar Structures:
Biological Unit for 3P8P: monomeric; determined by author and by software (PISA)
Molecular Components in 3P8P
Label Count Molecule
Protein (1 molecule)
N(g),n(g)-dimethylarginine Dimethylaminohydrolase 1(Gene symbol: DDAH1)
Molecule annotation
Chemical (1 molecule)
* Click molecule labels to explore molecular sequence information.

Citing MMDB