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 DOI: 10.2210/pdb3nli/pdb
• Related: 3NLD 3NLE 3NLF 3NLG 3NLH 3NLJ 3NLK 3NLM 3NLN 3NLO 3NLP 3NLQ 3NLR 3NLT 3NLU 3NLV 3NLW 3NLX 3NLY 3NLZ 3NM0
• Descriptor: Nitric oxide synthase, endothelial, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (9 entities in total)
• Functional Keywords: nitric oxide synthase, heme enzyme, substrate inhibitor, oxidoreductase
• Biological source: Bos taurus (bovine,cow,domestic cattle,domestic cow)
• Total number of polymer chains: 2
• Total formula weight: 102526.29

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 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

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

Experimental method

X-RAY DIFFRACTION (1.98 Å)