3NLP
Structure of neuronal nitric oxide synthase D597N/M336V mutant heme domain in complex with 6-{{(3'S,4'S)-3'-[2"-(3'''-fluorophenethylamino)ethoxy]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine
Summary for 3NLP
| Entry DOI | 10.2210/pdb3nlp/pdb |
| Related | 3NLD 3NLE 3NLF 3NLG 3NLH 3NLI 3NLJ 3NLK 3NLM 3NLN 3NLO 3NLQ 3NLR 3NLT 3NLU 3NLV 3NLW 3NLX 3NLY 3NLZ 3NM0 |
| Descriptor | Nitric oxide synthase, brain, PROTOPORPHYRIN IX CONTAINING FE, GLYCEROL, ... (8 entities in total) |
| Functional Keywords | nitric oxide synthase, inhibitor, heme enzyme, oxidoreductase |
| Biological source | Rattus norvegicus (brown rat,rat,rats) |
| Total number of polymer chains | 2 |
| Total formula weight | 100387.07 |
| Authors | Li, H.,Delker, S.L.,Poulos, T.L. (deposition date: 2010-06-21, release date: 2010-11-03, Last modification date: 2023-09-06) |
| Primary citation | Ji, H.,Delker, S.L.,Li, H.,Martasek, P.,Roman, L.J.,Poulos, T.L.,Silverman, R.B. Exploration of the Active Site of Neuronal Nitric Oxide Synthase by the Design and Synthesis of Pyrrolidinomethyl 2-Aminopyridine Derivatives. J.Med.Chem., 53:7804-7824, 2010 Cited by PubMed Abstract: Neuronal nitric oxide synthase (nNOS) represents an important therapeutic target for the prevention of brain injury and the treatment of various neurodegenerative disorders. A series of trans-substituted amino pyrrolidinomethyl 2-aminopyridine derivatives (8-34) was designed and synthesized. A structure-activity relationship analysis led to the discovery of low nanomolar nNOS inhibitors ((±)-32 and (±)-34) with more than 1000-fold selectivity for nNOS over eNOS. Four enantiomerically pure isomers of 3'-[2''-(3'''-fluorophenethylamino)ethoxy]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine (4) also were synthesized. It was found that (3'R,4'R)-4 can induce enzyme elasticity to generate a new "hot spot" for ligand binding. The inhibitor adopts a unique binding mode, the same as that observed for (3'R,4'R)-3'-[2''-(3'''-fluorophenethylamino)ethylamino]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine ((3'R,4'R)-3) (J. Am. Chem. Soc. 2010, 132 (15), 5437 - 5442). On the basis of structure-activity relationships of 8-34 and different binding conformations of the cis and trans isomers of 3 and 4, critical structural requirements of the NOS active site for ligand binding are revealed. PubMed: 20958055DOI: 10.1021/jm100947x PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.02 Å) |
Structure validation
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