Discovering new drug-targeting sites on flexible multidomain protein kinases: Combining segmental isotopic and site-directed spin labeling for nuclear magnetic resonance detection of interfacial clefts.

Research output: Contribution to journalReview article

5 Scopus citations

Abstract

A novel structure-based approach to study the structure and dynamics of flexible multi-domain monomeric protein kinases, which otherwise do not yield diffraction quality crystals, is described. A combination of segmental 15N-isotopic labeling of a regulatory domain with site-directed paramagnetic nitroxide spin labeling of the kinase domain is employed. Nuclear magnetic resonance studies of the enhancement of amide proton relaxation rates of the 15N-isotopically labeled regulatory domain caused by insertion of the paramagnetic nitroxide spin label on the kinase domain provide long-range distance restraints for determination of both the average positional structure and the relative flexibility exhibited between the two contiguous domains. Clefts and crevices detected around the dynamic domain-domain interface provide new targeting sites for tethered-based extension of current small-molecule lead compounds to produce more potent and selective pharmaceutical agents.

Original languageEnglish (US)
Pages (from-to)199-225
Number of pages27
JournalMethods in molecular biology (Clifton, N.J.)
Volume316
StatePublished - 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

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