Structural highlights
4imx is a 2 chain structure with sequence from Bos taurus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Ligands: | , , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
NOS3_BOVIN Produces nitric oxide (NO) which is implicated in vascular smooth muscle relaxation through a cGMP-mediated signal transduction pathway. NO mediates vascular endothelial growth factor (VEGF)-induced angiogenesis in coronary vessels and promotes blood clotting through the activation of platelets.
Publication Abstract from PubMed
Nitric oxide synthases (NOSs) comprise three closely related isoforms that catalyze the oxidation of l-arginine to l-citrulline and the important second messenger nitric oxide (NO). Pharmacological selective inhibition of neuronal NOS (nNOS) has the potential to be therapeutically beneficial in various neurodegenerative diseases. Here, we present a structure-guided, selective nNOS inhibitor design based on the crystal structure of lead compound 1 in nNOS. The best inhibitor, 7, exhibited low nanomolar inhibitory potency and good isoform selectivities (nNOS over eNOS and iNOS are 472-fold and 239-fold, respectively). Consistent with the good selectivity, 7 binds to nNOS and eNOS with different binding modes. The distinctly different binding modes of 7, driven by the critical residue Asp597 in nNOS, offers compelling insight to explain its isozyme selectivity, which should guide future drug design programs.
Structure-guided design of selective inhibitors of neuronal nitric oxide synthase.,Huang H, Li H, Martasek P, Roman LJ, Poulos TL, Silverman RB J Med Chem. 2013 Apr 11;56(7):3024-32. doi: 10.1021/jm4000984. Epub 2013 Mar 28. PMID:23451760[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Huang H, Li H, Martasek P, Roman LJ, Poulos TL, Silverman RB. Structure-guided design of selective inhibitors of neuronal nitric oxide synthase. J Med Chem. 2013 Apr 11;56(7):3024-32. doi: 10.1021/jm4000984. Epub 2013 Mar 28. PMID:23451760 doi:http://dx.doi.org/10.1021/jm4000984
