3JWS
Structure of neuronal nitric oxide synthase R349A mutant heme domain complexed with N1-[(3' S,4'S)-4'-((6"-amino-4"-methylpyridin-2"-yl)methyl)pyrrolidin-3'-yl]-N2-(3'-fluorophenethyl)ethane-1,2-diamine tetrahydrochloride
Summary for 3JWS
| Entry DOI | 10.2210/pdb3jws/pdb |
| Related | 3JW0 3JW1 3JW2 3JW3 3JW4 3JW5 3JW6 3JWT 3JWU 3JWV 3JWW 3JWX 3JWY 3JWZ |
| Descriptor | Nitric oxide synthase, brain, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (7 entities in total) |
| Functional Keywords | heme enzyme, substrate inhibitor, oxidoreductase |
| Biological source | Rattus norvegicus (rat) |
| Total number of polymer chains | 2 |
| Total formula weight | 100094.78 |
| Authors | Delker, S.L.,Li, H.,Poulos, T.L. (deposition date: 2009-09-18, release date: 2010-05-05, Last modification date: 2024-02-21) |
| Primary citation | Delker, S.L.,Ji, H.,Li, H.,Jamal, J.,Fang, J.,Xue, F.,Silverman, R.B.,Poulos, T.L. Unexpected binding modes of nitric oxide synthase inhibitors effective in the prevention of a cerebral palsy phenotype in an animal model. J.Am.Chem.Soc., 132:5437-5442, 2010 Cited by PubMed 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. PubMed: 20337441DOI: 10.1021/ja910228a PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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