1dmk
From Proteopedia
(New page: 200px<br /><applet load="1dmk" size="450" color="white" frame="true" align="right" spinBox="true" caption="1dmk, resolution 1.90Å" /> '''BOVINE ENDOTHELIAL N...) |
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| - | [[Image:1dmk.gif|left|200px]]<br /><applet load="1dmk" size=" | + | [[Image:1dmk.gif|left|200px]]<br /><applet load="1dmk" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1dmk, resolution 1.90Å" /> | caption="1dmk, resolution 1.90Å" /> | ||
'''BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 4-AMINO-6-PHENYL-TETRAHYDROPTERIDINE'''<br /> | '''BOVINE ENDOTHELIAL NITRIC OXIDE SYNTHASE HEME DOMAIN COMPLEXED WITH 4-AMINO-6-PHENYL-TETRAHYDROPTERIDINE'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Pathological nitric oxide (NO) generation in sepsis, inflammation, and | + | 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== | ==About this Structure== | ||
| - | 1DMK is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with ACT, CAC, ZN, HEM, AP6 and ITU as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http:// | + | 1DMK is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus] with <scene name='pdbligand=ACT:'>ACT</scene>, <scene name='pdbligand=CAC:'>CAC</scene>, <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=HEM:'>HEM</scene>, <scene name='pdbligand=AP6:'>AP6</scene> and <scene name='pdbligand=ITU:'>ITU</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DMK OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Al-Masoudi, N.]] | [[Category: Al-Masoudi, N.]] | ||
[[Category: Berg, M.]] | [[Category: Berg, M.]] | ||
| - | [[Category: Frohlich, L | + | [[Category: Frohlich, L G.]] |
[[Category: Gerwig, R.]] | [[Category: Gerwig, R.]] | ||
[[Category: Groehn, V.]] | [[Category: Groehn, V.]] | ||
| Line 23: | Line 23: | ||
[[Category: Li, H.]] | [[Category: Li, H.]] | ||
[[Category: Martasek, P.]] | [[Category: Martasek, P.]] | ||
| - | [[Category: Masters, B | + | [[Category: Masters, B S.]] |
[[Category: Matter, H.]] | [[Category: Matter, H.]] | ||
[[Category: Mohr, D.]] | [[Category: Mohr, D.]] | ||
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[[Category: Pfleiderer, W.]] | [[Category: Pfleiderer, W.]] | ||
[[Category: Poulos, T.]] | [[Category: Poulos, T.]] | ||
| - | [[Category: Raman, C | + | [[Category: Raman, C S.]] |
| - | [[Category: Schmidt, H | + | [[Category: Schmidt, H H.]] |
[[Category: Schnabel, J.]] | [[Category: Schnabel, J.]] | ||
[[Category: Strobel, H.]] | [[Category: Strobel, H.]] | ||
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[[Category: alpha-beta fold]] | [[Category: alpha-beta fold]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:18:11 2008'' |
Revision as of 10:18, 21 February 2008
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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 , , , , and 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
Page seeded by OCA on Thu Feb 21 12:18:11 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
