3NLH: Structure Of Endothelial Nitric Oxide Synthase Heme Domain N368d Mutant Complexed With 6-{{(3's,4's)-3'-[2"-(3'''- Fluorophenethylamino)ethoxy]pyrrolidin-4'-Yl}methyl}-4-Methylpyridin- 2-Amine

Citation:
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.
PDB ID: 3NLHDownload
MMDB ID: 85920
PDB Deposition Date: 2010/6/21
Updated in MMDB: 2010/11
Experimental Method:
x-ray diffraction
Resolution: 2.1  Å
Source Organism:
Similar Structures:
Biological Unit for 3NLH: dimeric; determined by author and by software (PISA)
Molecular Components in 3NLH
Label Count Molecule
Proteins (2 molecules)
2
Nitric Oxide Synthase, Endothelial(Gene symbol: NOS3)
Molecule annotation
Chemicals (13 molecules)
1
2
2
2
3
2
4
2
5
2
6
2
7
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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