2hx3

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{{STRUCTURE_2hx3| PDB=2hx3 | SCENE= }}
{{STRUCTURE_2hx3| PDB=2hx3 | SCENE= }}
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'''Rat nNOS heme domain complexed with (4S)-N-{4-Amino-5-[(2-aminoethyl)-hydroxyamino]-pentyl}-N'-nitroguanidine'''
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===Rat nNOS heme domain complexed with (4S)-N-{4-Amino-5-[(2-aminoethyl)-hydroxyamino]-pentyl}-N'-nitroguanidine===
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==Overview==
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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.
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{{ABSTRACT_PUBMED_17425297}}
==About this Structure==
==About this Structure==
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==Reference==
==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 May 3;50(9):2089-99. Epub 2007 Apr 11. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17425297 17425297]
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 May 3;50(9):2089-99. Epub 2007 Apr 11. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17425297 17425297]
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Structural basis for dipeptide amide isoform-selective inhibition of neuronal nitric oxide synthase., Flinspach ML, Li H, Jamal J, Yang W, Huang H, Hah JM, Gomez-Vidal JA, Litzinger EA, Silverman RB, Poulos TL, Nat Struct Mol Biol. 2004 Jan;11(1):54-9. Epub 2003 Dec 29. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14718923 14718923]
[[Category: Nitric-oxide synthase]]
[[Category: Nitric-oxide synthase]]
[[Category: Rattus norvegicus]]
[[Category: Rattus norvegicus]]
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[[Category: Inhibitor]]
[[Category: Inhibitor]]
[[Category: Nitric oxide synthase]]
[[Category: Nitric oxide synthase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 14:42:20 2008''

Revision as of 11:42, 27 July 2008

Image:2hx3.png

Template:STRUCTURE 2hx3

Rat nNOS heme domain complexed with (4S)-N-{4-Amino-5-[(2-aminoethyl)-hydroxyamino]-pentyl}-N'-nitroguanidine

Template:ABSTRACT PUBMED 17425297

About this Structure

2HX3 is a Single protein structure of sequence from Rattus norvegicus. 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 May 3;50(9):2089-99. Epub 2007 Apr 11. PMID:17425297

Structural basis for dipeptide amide isoform-selective inhibition of neuronal nitric oxide synthase., Flinspach ML, Li H, Jamal J, Yang W, Huang H, Hah JM, Gomez-Vidal JA, Litzinger EA, Silverman RB, Poulos TL, Nat Struct Mol Biol. 2004 Jan;11(1):54-9. Epub 2003 Dec 29. PMID:14718923

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