3E65

Murine INOS dimer with HEME, pterin and inhibitor AR-C120011

3E65 の概要

• エントリーDOI: 10.2210/pdb3e65/pdb
• 分子名称: Nitric oxide synthase, inducible, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (5 entities in total)
• 機能のキーワード: dimer, inducible nitric oxide synthase, calmodulin-binding, fad, fmn, heme, iron, metal-binding, nadp, oxidoreductase, polymorphism, zinc
• 由来する生物種: Mus musculus (mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 102692.21

構造登録者

Rosenfeld, R.J.,Garcin, E.D.,Getzoff, E.D. (登録日: 2008-08-14, 公開日: 2008-10-07, 最終更新日: 2023-08-30)

主引用文献

Garcin, E.D.,Arvai, A.S.,Rosenfeld, R.J.,Kroeger, M.D.,Crane, B.R.,Andersson, G.,Andrews, G.,Hamley, P.J.,Mallinder, P.R.,Nicholls, D.J.,St-Gallay, S.A.,Tinker, A.C.,Gensmantel, N.P.,Mete, A.,Cheshire, D.R.,Connolly, S.,Stuehr, D.J.,Aberg, A.,Wallace, A.V.,Tainer, J.A.,Getzoff, E.D.
Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase.
Nat.Chem.Biol., 4:700-707, 2008

PubMed Abstract: Nitric oxide synthase (NOS) enzymes synthesize nitric oxide, a signal for vasodilatation and neurotransmission at low concentrations and a defensive cytotoxin at higher concentrations. The high active site conservation among all three NOS isozymes hinders the design of selective NOS inhibitors to treat inflammation, arthritis, stroke, septic shock and cancer. Our crystal structures and mutagenesis results identified an isozyme-specific induced-fit binding mode linking a cascade of conformational changes to a new specificity pocket. Plasticity of an isozyme-specific triad of distant second- and third-shell residues modulates conformational changes of invariant first-shell residues to determine inhibitor selectivity. To design potent and selective NOS inhibitors, we developed the anchored plasticity approach: anchor an inhibitor core in a conserved binding pocket, then extend rigid bulky substituents toward remote specificity pockets, which become accessible upon conformational changes of flexible residues. This approach exemplifies general principles for the design of selective enzyme inhibitors that overcome strong active site conservation.

PubMed: 18849972
DOI: 10.1038/nchembio.115

実験手法

X-RAY DIFFRACTION (2.05 Å)