2hx3
From Proteopedia
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|PDB= 2hx3 |SIZE=350|CAPTION= <scene name='initialview01'>2hx3</scene>, resolution 2.00Å | |PDB= 2hx3 |SIZE=350|CAPTION= <scene name='initialview01'>2hx3</scene>, resolution 2.00Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand= | + | |LIGAND= <scene name='pdbligand=3HX:(4S)-N-{4-AMINO-5-[(2-AMINOETHYL)(HYDROXYAMINO]-PENTYL}-N'-NITROGUANIDINE'>3HX</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=BH4:(6R,1'R,2'S)-5,6,7,8+TETRAHYDROBIOPTERIN'>BH4</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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] | + | |ACTIVITY= <span class='plainlinks'>[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] </span> |
|GENE= Nos1, Bnos ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Rattus norvegicus]) | |GENE= Nos1, Bnos ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Rattus norvegicus]) | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1p6i|1P6I]], [[2hx2|2HX2]], [[2hx4|2HX4]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2hx3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2hx3 OCA], [http://www.ebi.ac.uk/pdbsum/2hx3 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2hx3 RCSB]</span> | ||
}} | }} | ||
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[[Category: Li, H.]] | [[Category: Li, H.]] | ||
[[Category: Poulos, T L.]] | [[Category: Poulos, T L.]] | ||
| - | [[Category: 3HX]] | ||
| - | [[Category: ACT]] | ||
| - | [[Category: BH4]] | ||
| - | [[Category: HEM]] | ||
| - | [[Category: ZN]] | ||
[[Category: heme enzyme]] | [[Category: heme enzyme]] | ||
[[Category: inhibitor]] | [[Category: inhibitor]] | ||
[[Category: nitric oxide synthase]] | [[Category: nitric oxide synthase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:36:42 2008'' |
Revision as of 00:36, 31 March 2008
| |||||||
| , resolution 2.00Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , , , , | ||||||
| Gene: | Nos1, Bnos (Rattus norvegicus) | ||||||
| Activity: | Nitric-oxide synthase, with EC number 1.14.13.39 | ||||||
| Related: | 1P6I, 2HX2, 2HX4
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Rat nNOS 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
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
Page seeded by OCA on Mon Mar 31 03:36:42 2008
