1VAG

Neuronal nitric oxide synthase oxygenase domain complexed with the inhibitor AR-R17477

1VAG の概要

• エントリーDOI: 10.2210/pdb1vag/pdb
• 関連するPDBエントリー: 1QW4 1QW5 1QW6 1QWC 1VAF
• 分子名称: Nitric-oxide synthase, brain, ZINC ION, PROTOPORPHYRIN IX CONTAINING FE, ... (6 entities in total)
• 機能のキーワード: rat nnosoxy complex with ar-r17477, oxidoreductase
• 由来する生物種: Rattus norvegicus (Norway rat)
• 細胞内の位置: Cell membrane, sarcolemma ; Peripheral membrane protein : P29476
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 49873.26

構造登録者

Fedorov, R.,Vasan, R.,Ghosh, D.K.,Schlichting, I. (登録日: 2004-02-16, 公開日: 2004-06-01, 最終更新日: 2023-10-25)

主引用文献

Fedorov, R.,Vasan, R.,Ghosh, D.K.,Schlichting, I.
Structures of nitric oxide synthase isoforms complexed with the inhibitor AR-R17477 suggest a rational basis for specificity and inhibitor design
Proc.Natl.Acad.Sci.USA, 101:5892-5897, 2004

PubMed Abstract: The high level of amino acid conservation and structural similarity of the substrate-binding sites of the oxygenase domains of the nitric oxide synthase (NOS) isoforms (eNOSoxy, iNOSoxy, nNOSoxy) make the interpretation of the structural basis of inhibitor isoform specificity a challenge, and provide few clues for the design of new selective compounds. Crystal structures of iNOSoxy and nNOSoxy complexed with the neuronal NOS-specific inhibitor AR-R17447 suggest that specificity is provided by the interaction of the chlorophenyl group with an isoform-unique substrate access channel residue (L337 in rat neuronal NOS, N115 in mouse inducible NOS). This is confirmed by biochemical analysis of site-directed mutants. Inhibitors combining guanidinium-like structural motifs with long chains specifically targeting this residue are good candidates for rational isoform-specific drug design. Based on this finding, modifications of AR-R17447 to improve the specificity for the human isoforms are suggested.

PubMed: 15071192
DOI: 10.1073/pnas.0306588101

実験手法

X-RAY DIFFRACTION (2 Å)