2hx2
From Proteopedia
(New page: 200px<br /><applet load="2hx2" size="450" color="white" frame="true" align="right" spinBox="true" caption="2hx2, resolution 1.95Å" /> '''Bovine eNOS heme dom...) |
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| - | [[Image:2hx2.gif|left|200px]]<br /><applet load="2hx2" size=" | + | [[Image:2hx2.gif|left|200px]]<br /><applet load="2hx2" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2hx2, resolution 1.95Å" /> | caption="2hx2, resolution 1.95Å" /> | ||
'''Bovine eNOS heme domain complexed with (4S)-N-{4-Amino-5-[(2-aminoethyl)-hydroxyamino]-pentyl}-N'-nitroguanidine'''<br /> | '''Bovine eNOS heme domain complexed with (4S)-N-{4-Amino-5-[(2-aminoethyl)-hydroxyamino]-pentyl}-N'-nitroguanidine'''<br /> | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2HX2 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 CAC, ACT, ZN, HEM, BH4, 3HX and GOL 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:// | + | 2HX2 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=CAC:'>CAC</scene>, <scene name='pdbligand=ACT:'>ACT</scene>, <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=HEM:'>HEM</scene>, <scene name='pdbligand=BH4:'>BH4</scene>, <scene name='pdbligand=3HX:'>3HX</scene> and <scene name='pdbligand=GOL:'>GOL</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=2HX2 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: nitric oxide synthase]] | [[Category: nitric oxide synthase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 15:09:15 2008'' |
Revision as of 13:09, 23 January 2008
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Bovine eNOS heme domain complexed with (4S)-N-{4-Amino-5-[(2-aminoethyl)-hydroxyamino]-pentyl}-N'-nitroguanidine
Overview
The neuronal isoform of nitric oxide synthase (nNOS), the enzyme, responsible for the production of nitric oxide in the central nervous, system, represents an attractive target for the treatment of various, neurodegenerative disorders. X-ray crystal structures of complexes of nNOS, with two nNOS-selective inhibitors, (4S)-N-{4-amino-5-[(2-aminoethylamino]pentyl}-N'-nitroguanidine (1) and, 4-N-(Nomega-nitro-l-argininyl)-trans-4-amino-l-proline amide (2), led to, the discovery of a conserved structural water molecule that was hydrogen, bonded between the two heme propionates and the inhibitors (Figure 2). On, the basis of this observation, we hypothesized that by attaching a, hydrogen bond donor group to the amide nitrogen of 2 or to the secondary, amine nitrogen of 1, the inhibitor molecules could displace the structural, water molecule and obtain a direct interaction with the heme cofactor. To, test this hypothesis, peptidomimetic analogues 3-5, which have either an, N-hydroxyl (3 and 5) or N-amino (4) donor group, were designed and, synthesized. X-ray crystal structures of nNOS with inhibitors 3 and 5, bound verified that the N-hydroxyl group had, indeed, displaced the, structural water molecule and provided a direct interaction with the heme, propionate moiety (Figures 5 and 6). Surprisingly, in vitro activity assay, results indicated that the addition of a hydroxyl group (3) only increased, the potency slightly against the neuronal isoform over the parent compound, (1). Rationalizations for the small increase in potency are consistent, with other changes in the crystal structures.
About this Structure
2HX2 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
Structure-Based Design and Synthesis of N(omega)-Nitro-l-Arginine-Containing Peptidomimetics as Selective Inhibitors of Neuronal Nitric Oxide Synthase. Displacement of the Heme Structural Water., Seo J, Igarashi J, Li H, Martasek P, Roman LJ, Poulos TL, Silverman RB, J Med Chem. 2007 Apr 11;. PMID:17425297
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Categories: Bos taurus | Nitric-oxide synthase | Single protein | Igarashi, J. | Li, H. | Poulos, T.L. | 3HX | ACT | BH4 | CAC | GOL | HEM | ZN | Heme enzyme | Inhibitor | Nitric oxide synthase
