title: Mechanism and specificity of pentachloropseudilin-mediated inhibition of myosin motor activity.
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.
authors.affiliation: Research Centre for Structural Analysis, Hannover Medical School, Hannover, Germany.
authors.forename: Krishna
authors.initials: K
authors.lastname: Chinthalapudi
authors.forename: Manuel H
authors.initials: MH
authors.lastname: Taft
authors.forename: René
authors.initials: R
authors.lastname: Martin
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Heissler
authors.forename: Matthias
authors.initials: M
authors.lastname: Preller
authors.forename: Falk K
authors.initials: FK
authors.lastname: Hartmann
authors.forename: Hemma
authors.initials: H
authors.lastname: Brandstaetter
authors.forename: John
authors.initials: J
authors.lastname: Kendrick-Jones
authors.forename: Georgios
authors.initials: G
authors.lastname: Tsiavaliaris
authors.forename: Herwig O
authors.initials: HO
authors.lastname: Gutzeit
authors.forename: Roman
authors.initials: R
authors.lastname: Fedorov
authors.forename: Folma
authors.initials: F
authors.lastname: Buss
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Knölker
authors.forename: Lynne M
authors.initials: LM
authors.lastname: Coluccio
authors.forename: Dietmar J
authors.initials: DJ
authors.lastname: Manstein
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D002645:Chickens; D004023:Dictyostelium / Q000201:enzymology*; D006843:Hydrocarbons, Chlorinated / Q000737:chemistry*; D008958:Models, Molecular; D009218:Myosins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011758:Pyrroles / Q000737:chemistry*; D011817:Rabbits; D051381:Rats
chemical_list: D006843:Hydrocarbons, Chlorinated; D011758:Pyrroles; C493099:pentachloropseudilin; D009218:Myosins