Protein Name

Hemeoxygenase domain of cytokine-inducible nitric oxide syntase



Biological Context

Nitric oxide (NO) is a gaseous signaling molecule which regulates numerous physiological functions such as blood flow and neural activity. NO is synthesized by the NO syntase via a heme-based two-step oxidation of L-arginine (L-Arg).

L-Arg + O2 + NADPH + H+ → NOH-L-Arg + H2O + NADP+ NOH-L-Arg + O2 + 1/2 (NADPH + H+) → L-citrulline + NO + H2O + 1/2 NADP+

There are three types of NOSs; neural (nNOS), endothelial (eNOS) and cytokine-inducible (iNOS) isozymes. Although the tissue distribution and the function of them are distinct, the overall protein structure is similar. They share (1) N-terminal hemeoxygenase domain where the substrate L-Arg binds, (2) C-terminal reductase domain where the reductive cofactors (ex. NADPH) binds, and (3) an intervening calmodulin binding region that regulates electronic communication between hemeoxygenase- and reductase domains.

Structure Description



fig1. Overall structure of iNOSox

The hemeoxygenase domain of iNOS (iNOSox) is described here. iNOSox has unusual α-β fold that resembles a baseball catcher’s mitt for the left hand. Heme is accommodated within the “heme pocket” formed between the edge of central βsheet and the loop colored. This β structure based-heme pocket differs considerably from those of the other heme-based enzymes, which are largely α helical.


fig2. The heme pocket of iNOS

Two imidazoles (NOS inhibitor) bind to this iNOSox. This structure revealed the dual NOS inhibitory mechanism of imidazole. One imidazole (IM1) binds directly to the heme iron and makes no hydrogen bond to any protein residues. Because the electronic state of heme is critical for the oxidative reactions, IM1 binding to the heme inhibits the enzymatic activity. Another imidazole (IM2) interacts with E371 via a hydrogen bond. Because E371 is the L-Arg binding site, IM2 inhibits the substrate binding.

Protein Data Bank (PDB)



Crane, B.R. Arvai, A.S. Gachhui, R. Wu, C. Ghosh, D.K. Getzoff, E.D. Stuehr, D.J. Tainer, J.A.; "The structure of nitric oxide synthase oxygenase domain and inhibitor complexes."; Science; (1997) 278:425-431 PubMed:9334294.


author: Daisuke Ino

Japanese version:PDB:1NOS