2. Academic Validation
  3. Mechanism and specificity of pentachloropseudilin-mediated inhibition of myosin motor activity

Mechanism and specificity of pentachloropseudilin-mediated inhibition of myosin motor activity

  • J Biol Chem. 2011 Aug 26;286(34):29700-8. doi: 10.1074/jbc.M111.239210.
Krishna Chinthalapudi 1,  Manuel H Taft,  René Martin,  Sarah M Heissler,  Matthias Preller,  Falk K Hartmann,  Hemma Brandstaetter,  John Kendrick-Jones,  Georgios Tsiavaliaris,  Herwig O Gutzeit,  Roman Fedorov,  Folma Buss,  Hans-Joachim Knölker,  Lynne M Coluccio,  Dietmar J Manstein
Affiliations

Affiliation

  • 1 Research Centre for Structural Analysis, Hannover Medical School, Hannover, Germany.
PMID: 21680745 DOI: 10.1074/jbc.M111.239210
Abstract

Here, we report that the natural compound pentachloropseudilin (PClP) acts as a reversible and allosteric inhibitor of Myosin ATPase and motor activity. IC(50) values are in the range from 1 to 5 μm for mammalian class-1 myosins and greater than 90 μm for class-2 and class-5 myosins, and no inhibition was observed with class-6 and class-7 myosins. We show that in mammalian cells, PClP selectively inhibits myosin-1c function. To elucidate the structural basis for PClP-induced allosteric coupling and isoform-specific differences in the inhibitory potency of the compound, we used a multifaceted approach combining direct functional, crystallographic, and in silico modeling studies. Our results indicate that allosteric inhibition by PClP is mediated by the combined effects of global changes in protein dynamics and direct communication between the catalytic and allosteric sites via a cascade of small conformational changes along a conserved communication pathway.

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