1DMJ: Bovine Endothelial Nitric Oxide Synthase Heme Domain Complexed With 5, 6-cyclic-tetrahydropteridine

Citation:
Abstract
Pathological nitric oxide (NO) generation in sepsis, inflammation, and stroke may be therapeutically controlled by inhibiting NO synthases (NOS). Here we targeted the (6R)-5,6,7,8-tetrahydro-l-biopterin (H(4)Bip)-binding site of NOS, which, upon cofactor binding, maximally increases enzyme activity and NO production from substrate l-arginine. The first generation of H(4)Bip-based NOS inhibitors employed a 4-amino pharmacophore of H(4)Bip analogous to antifolates such as methotrexate. We developed a novel series of 4-oxo-pteridine derivatives that were screened for inhibition against neuronal NOS (NOS-I) and a structure-activity relationship was determined. To understand the structural basis for pterin antagonism, selected derivatives were docked into the NOS pterin binding cavity. Using a reduced 4-oxo-pteridine scaffold, derivatives with certain modifications such as electron-rich aromatic phenyl or benzoyl groups at the 5- and 6-positions, were discovered to markedly inhibit NOS-I, possibly due to hydrophobic and electrostatic interactions with Phe(462) and Ser(104), respectively, within the pterin binding pocket. One of the most effective 4-oxo compounds and, for comparisons an active 4-amino derivative, were then co-crystallized with the endothelial NOS (NOS-III) oxygenase domain and this structure solved to confirm the hypothetical binding modes. Collectively, these findings suggest (i) that, unlike the antifolate principle, the 4-amino substituent is not essential for developing pterin-based NOS inhibitors and (ii), provide a steric and electrostatic basis for their rational design.
PDB ID: 1DMJDownload
MMDB ID: 15021
PDB Deposition Date: 1999/12/14
Updated in MMDB: 2007/10
Experimental Method:
x-ray diffraction
Resolution: 2.35  Å
Source Organism:
Similar Structures:
Biological Unit for 1DMJ: dimeric; determined by author and by software (PISA)
Molecular Components in 1DMJ
Label Count Molecule
Proteins (2 molecules)
2
Nitric Oxide Synthase(Gene symbol: NOS3)
Molecule annotation
Chemicals (15 molecules)
1
4
2
2
3
1
4
2
5
2
6
2
7
2
* Click molecule labels to explore molecular sequence information.

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