Article abstract
Nature Chemical Biology 4, 700 - 707 (2008)
Published online: 12 October 2008 | doi:10.1038/nchembio.115
Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase
Elsa D Garcin1,5, Andrew S Arvai1, Robin J Rosenfeld1, Matt D Kroeger1,5, Brian R Crane1,5, Gunilla Andersson2, Glen Andrews3, Peter J Hamley3,5, Philip R Mallinder3, David J Nicholls3, Stephen A St-Gallay3, Alan C Tinker3,6, Nigel P Gensmantel3, Antonio Mete3, David R Cheshire3, Stephen Connolly3, Dennis J Stuehr4, Anders Åberg2,5, Alan V Wallace3, John A Tainer1 & Elizabeth D Getzoff1
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.
- The Scripps Research Institute, Department of Molecular Biology and Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Road, MB4, La Jolla, California 92037, USA.
- AstraZeneca Structural Chemistry Laboratory, AstraZeneca R&D Mölndal, Pepparedsleden 1, S-431 83 Mölndal, Sweden.
- AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK.
- Department of Pathobiology, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44106, USA.
- Present addresses: University of Maryland Baltimore County, Department of Chemistry and Biochemistry, 1000 Hilltop Circle, Baltimore, Maryland 21250, USA (E.D.Garcin); Takeda San Diego, 10410 Science Center Drive, San Diego, California 92121, USA (M.D.K.); Cornell University, Chemistry and Chemical Biology Department, Ithaca, New York 14853, USA (B.R.C.); Sanofi Aventis, Industriepark Höchst, G838, 65926 Frankfurt am Main, Germany (P.J.H.); and Sidec AB, Torshamnsgatan 30A, SE-164 40 Kista, Sweden (A.Å.).
- Deceased.
Correspondence to: Elsa D Garcin1,5 e-mail: egarcin@umbc.edu
Correspondence to: Elizabeth D Getzoff1 e-mail: edg@scripps.edu
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