3NNZ

Structure of rat neuronal nitric oxide synthase heme domain complexed with 6-(((3S,4S)-4-(2-(3-Fluorophenethylamino)ethoxy)pyrrolidin-3-yl)methyl)pyridin-2-amine

Summary for 3NNZ

• Entry DOI: 10.2210/pdb3nnz/pdb
• Related: 3NLD 3NLE 3NLF 3NLG 3NLH 3NLI 3NLJ 3NLK 3NLM 3NLN 3NLO 3NLP 3NLQ 3NLR 3NLT 3NLU 3NLV 3NLW 3NLX 3NLY 3NLZ 3NM0 3NNY
• Descriptor: Nitric oxide synthase, brain, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (7 entities in total)
• Functional Keywords: nitric oxide synthase, heme enzyme, inhibitor, oxidoreductase
• Biological source: Rattus norvegicus (brown rat,rat,rats)
• Cellular location: Cell membrane, sarcolemma ; Peripheral membrane protein : P29476
• Total number of polymer chains: 2
• Total formula weight: 100240.93

Authors

Li, H.,Poulos, T.L. (deposition date: 2010-06-24, release date: 2010-10-06, Last modification date: 2023-09-06)

Primary citation

Xue, F.,Li, H.,Fang, J.,Roman, L.J.,Martasek, P.,Poulos, T.L.,Silverman, R.B.
Peripheral but crucial: a hydrophobic pocket (Tyr(706), Leu(337), and Met(336)) for potent and selective inhibition of neuronal nitric oxide synthase.
Bioorg.Med.Chem.Lett., 20:6258-6261, 2010

PubMed Abstract: Selective inhibition of the neuronal isoform of nitric oxide synthase (nNOS) over endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) has become a promising strategy for the discovery of new therapeutic agents for neurodegenerative diseases. However, because of the high sequence homology of different isozymes in the substrate binding pocket, developing inhibitors with both potency and excellent isoform selectivity remains a challenging problem. Herein, we report the evaluation of a recently discovered peripheral hydrophobic pocket (Tyr(706), Leu(337), and Met(336)) that opens up upon inhibitor binding and its potential in designing potent and selective nNOS inhibitors using three compounds, 2a, 2b, and 3. Crystal structure results show that inhibitors 2a and 3 adopted the same binding mode as lead compound 1. We also found that hydrophobic interactions between the 4-methyl group of the aminopyridine ring of these compounds with the side chain of Met(336), as well as the π-π stacking interaction between the pyridinyl motif and the side chain of Tyr(706) are important for the high potency and selectivity of these nNOS inhibitors.

PubMed: 20833542
DOI: 10.1016/j.bmcl.2010.08.096

Experimental method

X-RAY DIFFRACTION (1.97 Å)