3E7G

Structure of human INOSOX with inhibitor AR-C95791

Summary for 3E7G

• Entry DOI: 10.2210/pdb3e7g/pdb
• Related: 3E65 3E67 3E68 3E6L 3E6N 3E6O 3E6T
• Descriptor: Nitric oxide synthase, inducible, ZINC ION, PROTOPORPHYRIN IX CONTAINING FE, ... (6 entities in total)
• Functional Keywords: nitric oxide, nos, heme, tetrahydrobiopterin, oxidoreductase, alternative splicing, calcium, calmodulin-binding, fad, fmn, iron, metal-binding, nadp, phosphoprotein, polymorphism, zinc
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 200814.55

Authors

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.,Stueh, D.J.,Aberg, A.,Wallace, A.V.,Tainer, J.A.,Getzoff, E.D. (deposition date: 2008-08-18, release date: 2008-10-07, Last modification date: 2024-02-21)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.2 Å)