Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form

Anchored plasticity opens doors for selective inhibitor design in nitric oxide synthase

Academic Article
uri icon
  • Overview
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

authors

  • Garcin, E. D.
  • Arvai, A. S.
  • Gunn, Robin Rosenfeld
  • Kroeger, M. D.
  • Crane, Brian 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, John
  • Getzoff, Elizabeth

publication date

  • November 2008

journal

  • Nature Chemical Biology  Journal

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.

subject areas

  • Amino Acid Sequence
  • Aminopyridines
  • Animals
  • Cattle
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Drug Design
  • Enzyme Inhibitors
  • Gene Expression
  • Humans
  • Inflammation
  • Isoenzymes
  • Male
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Mutation
  • Nitric Oxide Synthase
  • Quinazolines
  • Rats
scroll to property group menus

Identity

PubMed Central ID

  • PMC2868503

International Standard Serial Number (ISSN)

  • 1552-4450

Digital Object Identifier (DOI)

  • 10.1038/nchembio.115

PubMed ID

  • 18849972
scroll to property group menus

Additional Document Info

start page

  • 700

end page

  • 707

volume

  • 4

issue

  • 11

©2021 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support