3B3O

Structure of neuronal nos heme domain in complex with a inhibitor (+-)-n1-{cis-4'-[(6"-amino-4"-methylpyridin-2"-yl)methyl]pyrrolidin-3'-yl}-n2-(4'-chlorobenzyl)ethane-1,2-diamine

Summary for 3B3O

• Entry DOI: 10.2210/pdb3b3o/pdb
• Related: 3B3M 3B3N 3B3P
• Descriptor: Nitric oxide synthase, brain, ACETATE ION, ZINC ION, ... (7 entities in total)
• Functional Keywords: nitric oxide synthase, heme enzyme, inhibitor, alternative splicing, calmodulin-binding, cell projection, fad, fmn, iron, membrane, metal-binding, nadp, oxidoreductase
• Biological source: Rattus norvegicus (Rat)
• Total number of polymer chains: 2
• Total formula weight: 100271.87

Authors

Igarashi, J.,Li, H.,Poulos, T.L. (deposition date: 2007-10-22, release date: 2008-11-04, Last modification date: 2024-02-21)

Primary citation

Igarashi, J.,Li, H.,Jamal, J.,Ji, H.,Fang, J.,Lawton, G.R.,Silverman, R.B.,Poulos, T.L.
Crystal structures of constitutive nitric oxide synthases in complex with de novo designed inhibitors.
J.Med.Chem., 52:2060-2066, 2009

PubMed Abstract: New nitric oxide synthase (NOS) inhibitors were designed de novo with knowledge gathered from the studies on the nNOS-selective dipeptide inhibitors. Each of the new inhibitors consists of three fragments: an aminopyridine ring, a pyrrolidine, and a tail of various length and polarity. The in vitro inhibitory assays indicate good potency and isoform selectivity for some of the compounds. Crystal structures of these inhibitors bound to either wild type or mutant nNOS and eNOS have confirmed design expectations. The aminopyridine ring mimics the guanidinium group of L-arginine and functions as an anchor to place the compound in the NOS active site where it hydrogen bonds to a conserved Glu. The rigidity of the pyrrolidine ring places the pyrrolidine ring nitrogen between the same conserved Glu and the selective residue nNOS Asp597/eNOS Asn368, which results in similar interactions observed with the alpha-amino group of dipeptide inhibitors bound to nNOS. These structures provide additional information to help in the design of inhibitors with greater potency, physicochemical properties, and isoform selectivity.

PubMed: 19296678
DOI: 10.1021/jm900007a

Experimental method

X-RAY DIFFRACTION (2.05 Å)