3I4A

Crystal structure of dimethylarginine dimethylaminohydrolase-1 (DDAH-1) in complex with N5-(1-iminopropyl)-L-ornithine

Summary for 3I4A

• Entry DOI: 10.2210/pdb3i4a/pdb
• Related: 2JAI 2JAJ 3I2E
• Descriptor: N(G),N(G)-dimethylarginine dimethylaminohydrolase 1, N5-(1-iminopropyl)-L-ornithine (3 entities in total)
• Functional Keywords: ddah, hydrolase, nitric oxide synthase regulation, metal-binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 67621.46

Authors

Monzingo, A.F.,Wang, Y.,Hu, S.,Schaller, T.H.,Fast, W.,Robertus, J.D. (deposition date: 2009-07-01, release date: 2009-08-25, Last modification date: 2024-11-20)

Primary citation

Wang, Y.,Monzingo, A.F.,Hu, S.,Schaller, T.H.,Robertus, J.D.,Fast, W.
Developing dual and specific inhibitors of dimethylarginine dimethylaminohydrolase-1 and nitric oxide synthase: toward a targeted polypharmacology to control nitric oxide.
Biochemistry, 48:8624-8635, 2009

PubMed Abstract: 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 N5-(1-iminoethyl)-, N5-(1-iminopropyl)-, N5-(1-iminopentyl)- and N(5)-(1-iminohexyl)-l-ornithine for neuronal NOS (1.7, 3, 20, >1,900 microM, respectively) and DDAH-1 (990, 52, 7.5, 110 microM, respectively). A 1.9 A X-ray crystal structure of the N5-(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.

PubMed: 19663506
DOI: 10.1021/bi9007098

Experimental method

X-RAY DIFFRACTION (1.898 Å)