1dmk | pdb_00001dmk
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| 1dmk, resolution 1.90Å | |||||||||||||
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| Ligands: | ACT, CAC, ZN, HEM, AP6 and ITU | ||||||||||||
| Activity: | Nitric-oxide synthase, with EC number 1.14.13.39 | ||||||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||||||
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. 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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Proteopedia Page Contributors and Editors (what is this?)
- Pages with broken file links
- Bos taurus
- Nitric-oxide synthase
- Single protein
- Al-Masoudi, N.
- Berg, M.
- Frohlich, L G.
- Gerwig, R.
- Groehn, V.
- Kang, Y.
- Kotsonis, P.
- Li, H.
- Martasek, P.
- Masters, B S.
- Matter, H.
- Mohr, D.
- Munch, U.
- Pfleiderer, W.
- Poulos, T.
- Raman, C S.
- Schmidt, H H.
- Schnabel, J.
- Strobel, H.
- Taghavi-Moghadam, S.
- ACT
- AP6
- CAC
- HEM
- ITU
- ZN
- Alpha-beta fold
