1zvi
From Proteopedia
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'''Rat Neuronal Nitric Oxide Synthase Oxygenase Domain''' | '''Rat Neuronal Nitric Oxide Synthase Oxygenase Domain''' | ||
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[[Category: Schlichting, I.]] | [[Category: Schlichting, I.]] | ||
[[Category: Schmidt, H H.]] | [[Category: Schmidt, H H.]] | ||
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| - | [[Category: | + | [[Category: Targeting tetrahydrobiopterin binding site]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 18:07:34 2008'' | |
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Revision as of 15:07, 3 May 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. 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 Sat May 3 18:07:34 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. | Rat nnosoxy | Targeting tetrahydrobiopterin binding site
