3JT3

Structure of neuronal nitric oxide synthase heme domain complexed with N~5~-[2-(methylsulfanyl)ethanimidoyl]-L-ornithine

Summary for 3JT3

• Entry DOI: 10.2210/pdb3jt3/pdb
• Related: 3JT4 3JT5 3JT6 3JT7 3JT8 3JT9 3JTA
• Descriptor: Nitric oxide synthase, brain, PROTOPORPHYRIN IX CONTAINING FE, N~5~-[2-(methylsulfanyl)ethanimidoyl]-L-ornithine, ... (7 entities in total)
• Functional Keywords: nitric oxide synthase, heme-thiolate enzyme, substrate-analogue inhibitor, thioether heme ligand, alternative splicing, calmodulin-binding, cell membrane, cell projection, fad, fmn, heme, iron, membrane, metal-binding, nadp, oxidoreductase
• Biological source: Rattus norvegicus (brown rat,rat,rats)
• Total number of polymer chains: 2
• Total formula weight: 99962.63

Authors

Li, H.,Poulos, T.L. (deposition date: 2009-09-11, release date: 2010-01-12, Last modification date: 2023-09-06)

Primary citation

Martell, J.D.,Li, H.,Doukov, T.,Martasek, P.,Roman, L.J.,Soltis, M.,Poulos, T.L.,Silverman, R.B.
Heme-coordinating inhibitors of neuronal nitric oxide synthase. Iron-thioether coordination is stabilized by hydrophobic contacts without increased inhibitor potency.
J.Am.Chem.Soc., 132:798-806, 2010

PubMed Abstract: The heme-thioether ligand interaction often occurs between heme iron and native methionine ligands, but thioether-based heme-coordinating (type II) inhibitors are uncommon due to the difficulty in stabilizing the Fe-S bond. Here, a thioether-based inhibitor (3) of neuronal nitric oxide synthase (nNOS) was designed, and its binding was characterized by spectrophotometry and crystallography. A crystal structure of inhibitor 3 coordinated to heme iron was obtained, representing, to our knowledge, the first crystal structure of a thioether inhibitor complexed to any heme enzyme. A series of related potential inhibitors (4-8) also were evaluated. Compounds 4-8 were all found to be type I (non-heme-coordinating) inhibitors of ferric nNOS, but 4 and 6-8 were found to switch to type II upon heme reduction to the ferrous state, reflecting the higher affinity of thioethers for ferrous heme than for ferric heme. Contrary to what has been widely thought, thioether-heme ligation was found not to increase inhibitor potency, illustrating the intrinsic weakness of the thioether-ferric heme linkage. Subtle changes in the alkyl groups attached to the thioether sulfur caused drastic changes in the binding conformation, indicating that hydrophobic contacts play a crucial role in stabilizing the thioether-heme coordination.

PubMed: 20014790
DOI: 10.1021/ja908544f

Experimental method

X-RAY DIFFRACTION (2.15 Å)