3JWU: Structure of rat neuronal nitric oxide synthase R349A mutant heme domain in complex with N1-{(3'R,4'S)-4'-[(6"-amino-4"-methylpyridin-2"-yl)methyl]pyrrolidin-3'-yl}-N2-(3'-fluorophenethyl)ethane-1,2-diamine tetrahydrochloride

Citation:
Abstract
Selective inhibition of the neuronal isoform of nitric oxide synthase NOS (nNOS) has been shown to prevent brain injury and is important for the treatment of various neurodegenerative disorders. However, given the high active site conservation among all three NOS isoforms, the design of selective inhibitors is an extremely challenging problem. Here we present the structural basis for why novel and potent nNOS inhibitors exhibit the highest level of selectivity over eNOS reported so far (approximately 3,800-fold). By using a combination of crystallography, computational methods, and site-directed mutagenesis, we found that inhibitor chirality and an unanticipated structural change of the target enzyme control both the orientation and selectivity of these novel nNOS inhibitors. A new hot spot generated as a result of enzyme elasticity provides important information for the future fragment-based design of selective NOS inhibitors.
PDB ID: 3JWUDownload
MMDB ID: 81834
PDB Deposition Date: 2009/9/18
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 1.93  Å
Source Organism:
Similar Structures:
Biological Unit for 3JWU: dimeric; determined by author and by software (PISA)
Molecular Components in 3JWU
Label Count Molecule
Proteins (2 molecules)
2
Nitric Oxide Synthase, Brain(Gene symbol: Nos1)
Molecule annotation
Chemicals (9 molecules)
1
2
2
2
3
2
4
2
5
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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