1dmk
From Proteopedia
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'''BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 4-AMINO-6-PHENYL-TETRAHYDROPTERIDINE''' | '''BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 4-AMINO-6-PHENYL-TETRAHYDROPTERIDINE''' | ||
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[[Category: Strobel, H.]] | [[Category: Strobel, H.]] | ||
[[Category: Taghavi-Moghadam, S.]] | [[Category: Taghavi-Moghadam, S.]] | ||
| - | [[Category: | + | [[Category: Alpha-beta fold]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 14:01:24 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 11:01, 2 May 2008
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 Page seeded by OCA on Fri May 2 14:01:24 2008
Categories: 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. | Alpha-beta fold
