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1dmk
From Proteopedia
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| - | [[Image:1dmk.gif|left|200px]] | + | [[Image:1dmk.gif|left|200px]] |
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| - | '''BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 4-AMINO-6-PHENYL-TETRAHYDROPTERIDINE''' | + | {{Structure |
| + | |PDB= 1dmk |SIZE=350|CAPTION= <scene name='initialview01'>1dmk</scene>, resolution 1.90Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CAC:CACODYLATE+ION'>CAC</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=AP6:2,4-DIAMINO-6-PHENYL-5,6,7,8,-TETRAHYDROPTERIDINE'>AP6</scene> and <scene name='pdbligand=ITU:ETHYLISOTHIOUREA'>ITU</scene> | ||
| + | |ACTIVITY= [http://en.wikipedia.org/wiki/Nitric-oxide_synthase Nitric-oxide synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.39 1.14.13.39] | ||
| + | |GENE= | ||
| + | }} | ||
| + | |||
| + | '''BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 4-AMINO-6-PHENYL-TETRAHYDROPTERIDINE''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1DMK is a [ | + | 1DMK is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DMK OCA]. |
==Reference== | ==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:[http:// | + | 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:[http://www.ncbi.nlm.nih.gov/pubmed/11590164 11590164] |
[[Category: Bos taurus]] | [[Category: Bos taurus]] | ||
[[Category: Nitric-oxide synthase]] | [[Category: Nitric-oxide synthase]] | ||
| Line 42: | Line 51: | ||
[[Category: alpha-beta fold]] | [[Category: alpha-beta fold]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 10:40:50 2008'' |
Revision as of 08:40, 20 March 2008
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| , resolution 1.90Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , , , and | ||||||
| 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
Page seeded by OCA on Thu Mar 20 10:40:50 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. | ACT | AP6 | CAC | HEM | ITU | ZN | Alpha-beta fold
