1dmk

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spinqualitylabelsall models 1dmk, resolution 1.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 4-AMINO-6-PHENYL-TETRAHYDROPTERIDINE

Overview

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.

About this Structure

1DMK is a Single protein structure of sequence from Bos taurus with ACT, CAC, ZN, HEM, AP6 and ITU as ligands. Active as Nitric-oxide synthase, with EC number 1.14.13.39 Full crystallographic information is available from OCA.

Reference

Structural basis for pterin antagonism in nitric-oxide synthase. Development of novel 4-oxo-pteridine antagonists of (6R)-5,6,7,8-tetrahydrobiopterin., Kotsonis P, Frohlich LG, Raman CS, Li H, Berg M, Gerwig R, Groehn V, Kang Y, Al-Masoudi N, Taghavi-Moghadam S, Mohr D, Munch U, Schnabel J, Martasek P, Masters BS, Strobel H, Poulos T, Matter H, Pfleiderer W, Schmidt HH, J Biol Chem. 2001 Dec 28;276(52):49133-41. Epub 2001 Oct 5. PMID:11590164

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