4CU1: Structure Of Bovine Endothelial Nitric Oxide Synthase Heme Domain In Complex With 6-[(2s)-3-amino-2-{5-[2-(6-amino- 4-methylpyridin-2-yl)ethyl]pyridin-3-yl}propyl]-4- Methylpyridin-2-amine

Citation:
Abstract
Overproduction of NO by nNOS is implicated in the pathogenesis of diverse neuronal disorders. Since NO signaling is involved in diverse physiological functions, selective inhibition of nNOS over other isoforms is essential to minimize side effects. A series of alpha-amino functionalized aminopyridine derivatives (3-8) were designed to probe the structure-activity relationship between ligand, heme propionate, and H4B. Compound 8R was identified as the most potent and selective molecule of this study, exhibiting a Ki of 24 nM for nNOS, with 273-fold and 2822-fold selectivity against iNOS and eNOS, respectively. Although crystal structures of 8R complexed with nNOS and eNOS revealed a similar binding mode, the selectivity stems from the distinct electrostatic environments in two isoforms that result in much lower inhibitor binding free energy in nNOS than in eNOS. These findings provide a basis for further development of simple, but even more selective and potent, nNOS inhibitors.
PDB ID: 4CU1Download
MMDB ID: 119545
PDB Deposition Date: 2014/3/15
Updated in MMDB: 2014/06
Experimental Method:
x-ray diffraction
Resolution: 1.89  Å
Source Organism:
Similar Structures:
Biological Unit for 4CU1: dimeric; determined by author and by software (PISA)
Molecular Components in 4CU1
Label Count Molecule
Proteins (2 molecules)
1
Nitric Oxide Synthase, Endothelial(Gene symbol: NOS3)
Molecule annotation
1
Nitric Oxide Synthase, Endothelial(Gene symbol: NOS3)
Molecule annotation
Chemicals (11 molecules)
1
2
2
2
3
2
4
2
5
2
6
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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