Premium
Communication between the zinc and tetrahydrobiopterin binding sites in nitric oxide synthase (774.1)
Author(s) -
Chreifi Georges,
Li Huiying,
McInnes Craig,
Suckling Colin,
Poulos Thomas
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.774.1
Subject(s) - tetrahydrobiopterin , enos , chemistry , dimer , pterin , nitric oxide synthase , endothelial nos , stereochemistry , nitric oxide synthase type iii , cofactor , biochemistry , enzyme , organic chemistry
The nitric oxide synthase (NOS) dimer is stabilized by a Zn 2+ ion coordinated to symmetry related Cys residues exactly on the dimer axis. Each of the two essential tetrahydrobiopterin (H 4 B) molecules in the dimer interacts directly with the heme, and each H 4 B molecule is about 12 Å from the Zn 2+ . We have solved the crystal structures of the bovine endothelial NOS (eNOS) dimer oxygenase domain bound to three different pterin compounds and they reveal an intimate structural communication between the H 4 B and Zn 2+ sites. The structure of one of these compounds, WSG1002, bound to eNOS with varying levels of Zn 2+ , showed that WSG1002 and Zn 2+ cannot bind to eNOS simultaneously. WSG1002 both directly and indirectly disrupts hydrogen bonding between key residues in the zinc binding motif, resulting in destabilization of the dimer. Addition of excess Zn 2+ stabilizes the Zn 2+ site which decreases binding of WSG1002. These results have directed our attention to differences between eNOS and the other two mammalian NOS isoforms, neuronal NOS (nNOS) and inducible NOS (iNOS), that provide a structural basis for why the order of dimer stability is eNOS>nNOS>iNOS. Grant Funding Source : Supported by NIH