4IMS
Structure of rat neuronal nitric oxide synthase heme domain in complex with 6,6'-((5-(3-aminopropyl)-1,3-phenylene)bis(ethane-2,1-diyl))bis(4-methylpyridin-2-amine)
Summary for 4IMS
| Entry DOI | 10.2210/pdb4ims/pdb |
| Related | 4IMT 4IMU 4IMW 4IMX |
| Descriptor | Nitric oxide synthase, brain, PROTOPORPHYRIN IX CONTAINING FE, 6,6'-{[5-(3-aminopropyl)benzene-1,3-diyl]diethane-2,1-diyl}bis(4-methylpyridin-2-amine), ... (7 entities in total) |
| Functional Keywords | oxidoreductase nitric oxide synthase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Rattus norvegicus (rat) |
| Cellular location | Cell membrane, sarcolemma ; Peripheral membrane protein : P29476 |
| Total number of polymer chains | 2 |
| Total formula weight | 100121.28 |
| Authors | Li, H.,Poulos, T.L. (deposition date: 2013-01-03, release date: 2013-04-24, Last modification date: 2023-09-20) |
| Primary citation | Huang, H.,Li, H.,Martasek, P.,Roman, L.J.,Poulos, T.L.,Silverman, R.B. Structure-guided design of selective inhibitors of neuronal nitric oxide synthase. J.Med.Chem., 56:3024-3032, 2013 Cited by PubMed Abstract: 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. PubMed: 23451760DOI: 10.1021/jm4000984 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.15 Å) |
Structure validation
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