1zvi
From Proteopedia
(New page: 200px<br /><applet load="1zvi" size="450" color="white" frame="true" align="right" spinBox="true" caption="1zvi, resolution 2.0Å" /> '''Rat Neuronal Nitric O...) |
|||
| Line 1: | Line 1: | ||
| - | [[Image:1zvi.gif|left|200px]]<br /><applet load="1zvi" size=" | + | [[Image:1zvi.gif|left|200px]]<br /><applet load="1zvi" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1zvi, resolution 2.0Å" /> | caption="1zvi, resolution 2.0Å" /> | ||
'''Rat Neuronal Nitric Oxide Synthase Oxygenase Domain'''<br /> | '''Rat Neuronal Nitric Oxide Synthase Oxygenase Domain'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Nitric oxide synthesized from l-arginine by nitric oxide synthase isoforms | + | Nitric oxide synthesized from l-arginine by nitric oxide synthase isoforms (NOS-I-III) is physiologically important but also can be deleterious when overproduced. Selective NOS inhibitors are of clinical interest, given their differing pathophysiological roles. Here we describe our approach to target the unique NOS (6R,1'R,2'S)-5,6,7,8-tetrahydrobiopterin (H(4)Bip) binding site. By a combination of ligand- and structure-based design, the structure-activity relationship (SAR) for a focused set of 41 pteridine analogues on four scaffolds was developed, revealing selective NOS-I inhibitors. The X-ray crystal structure of rat NOS-I dimeric-oxygenase domain with H(4)Bip and l-arginine was determined and used for human isoform homology modeling. All available NOS structural information was subjected to comparative analysis of favorable protein-ligand interactions using the GRID/concensus principal component analysis (CPCA) approach to identify the isoform-specific interaction site. Our interpretation, based on protein structures, is in good agreement with the ligand SAR and thus permits the rational design of next-generation inhibitors targeting the H(4)Bip binding site with enhanced isoform selectivity for therapeutics in pathology with NO overproduction. |
==About this Structure== | ==About this Structure== | ||
| - | 1ZVI is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with ZN, HEM and H4B 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:// | + | 1ZVI is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=HEM:'>HEM</scene> and <scene name='pdbligand=H4B:'>H4B</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=1ZVI OCA]. |
==Reference== | ==Reference== | ||
| Line 16: | Line 16: | ||
[[Category: Fedorov, R.]] | [[Category: Fedorov, R.]] | ||
[[Category: Frey, A.]] | [[Category: Frey, A.]] | ||
| - | [[Category: Frohlich, L | + | [[Category: Frohlich, L G.]] |
| - | [[Category: Ghosh, D | + | [[Category: Ghosh, D K.]] |
[[Category: Hartmann, E.]] | [[Category: Hartmann, E.]] | ||
[[Category: Kotsonis, P.]] | [[Category: Kotsonis, P.]] | ||
| - | [[Category: Kumar, H | + | [[Category: Kumar, H S.]] |
[[Category: Matter, H.]] | [[Category: Matter, H.]] | ||
[[Category: Pfleiderer, W.]] | [[Category: Pfleiderer, W.]] | ||
| Line 26: | Line 26: | ||
[[Category: Scheurer, P.]] | [[Category: Scheurer, P.]] | ||
[[Category: Schlichting, I.]] | [[Category: Schlichting, I.]] | ||
| - | [[Category: Schmidt, H | + | [[Category: Schmidt, H H.]] |
[[Category: H4B]] | [[Category: H4B]] | ||
[[Category: HEM]] | [[Category: HEM]] | ||
| Line 33: | Line 33: | ||
[[Category: targeting tetrahydrobiopterin binding site]] | [[Category: targeting tetrahydrobiopterin binding site]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:19:27 2008'' |
Revision as of 14:19, 21 February 2008
|
Rat Neuronal Nitric Oxide Synthase Oxygenase Domain
Overview
Nitric oxide synthesized from l-arginine by nitric oxide synthase isoforms (NOS-I-III) is physiologically important but also can be deleterious when overproduced. Selective NOS inhibitors are of clinical interest, given their differing pathophysiological roles. Here we describe our approach to target the unique NOS (6R,1'R,2'S)-5,6,7,8-tetrahydrobiopterin (H(4)Bip) binding site. By a combination of ligand- and structure-based design, the structure-activity relationship (SAR) for a focused set of 41 pteridine analogues on four scaffolds was developed, revealing selective NOS-I inhibitors. The X-ray crystal structure of rat NOS-I dimeric-oxygenase domain with H(4)Bip and l-arginine was determined and used for human isoform homology modeling. All available NOS structural information was subjected to comparative analysis of favorable protein-ligand interactions using the GRID/concensus principal component analysis (CPCA) approach to identify the isoform-specific interaction site. Our interpretation, based on protein structures, is in good agreement with the ligand SAR and thus permits the rational design of next-generation inhibitors targeting the H(4)Bip binding site with enhanced isoform selectivity for therapeutics in pathology with NO overproduction.
About this Structure
1ZVI is a Single protein structure of sequence from Rattus norvegicus 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 analysis of isoform-specific inhibitors targeting the tetrahydrobiopterin binding site of human nitric oxide synthases., Matter H, Kumar HS, Fedorov R, Frey A, Kotsonis P, Hartmann E, Frohlich LG, Reif A, Pfleiderer W, Scheurer P, Ghosh DK, Schlichting I, Schmidt HH, J Med Chem. 2005 Jul 28;48(15):4783-92. PMID:16033258
Page seeded by OCA on Thu Feb 21 16:19:27 2008
Categories: Nitric-oxide synthase | Rattus norvegicus | Single protein | Fedorov, R. | Frey, A. | Frohlich, L G. | Ghosh, D K. | Hartmann, E. | Kotsonis, P. | Kumar, H S. | Matter, H. | Pfleiderer, W. | Reif, A. | Scheurer, P. | Schlichting, I. | Schmidt, H H. | H4B | HEM | ZN | Rat nnosoxy | Targeting tetrahydrobiopterin binding site
