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3NLI

Structure of endothelial nitric oxide synthase N368D mutant heme domain complexed with 6-{{(3'R,4'R)-3'-[2"-(3'''-fluorophenethylamino)ethoxy]pyrrolidin-4'-yl}methyl}-4-methylpyridin-2-amine

Summary for 3NLI
Entry DOI10.2210/pdb3nli/pdb
Related3NLD 3NLE 3NLF 3NLG 3NLH 3NLJ 3NLK 3NLM 3NLN 3NLO 3NLP 3NLQ 3NLR 3NLT 3NLU 3NLV 3NLW 3NLX 3NLY 3NLZ 3NM0
DescriptorNitric oxide synthase, endothelial, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (9 entities in total)
Functional Keywordsnitric oxide synthase, heme enzyme, substrate inhibitor, oxidoreductase
Biological sourceBos taurus (bovine,cow,domestic cattle,domestic cow)
Total number of polymer chains2
Total formula weight102526.29
Authors
Delker, S.L.,Li, H.,Poulos, T.L. (deposition date: 2010-06-21, release date: 2010-11-03, Last modification date: 2024-02-21)
Primary citationJi, 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: 20958055
DOI: 10.1021/jm100947x
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.98 Å)
Structure validation

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