Title

The mechanism of pentabromopseudilin inhibition of myosin motor activity

Document Type

Article

Peer Reviewed

1

Publication Date

1-1-2009

Journal, Book or Conference Title

Nature structural & molecular biology

NLM Title Abbreviation

Nat Struct Mol Biol

PubMed ID

19122661

DOI

doi:10.1038/nsmb.1542

Abstract

We have identified pentabromopseudilin (PBP) as a potent inhibitor of myosin-dependent processes such as isometric tension development and unloaded shortening velocity. PBP-induced reductions in the rate constants for ATP binding, ATP hydrolysis and ADP dissociation extend the time required per myosin ATPase cycle in the absence and presence of actin. Additionally, coupling between the actin and nucleotide binding sites is reduced in the presence of the inhibitor. The selectivity of PBP differs from that observed with other myosin inhibitors. To elucidate the binding mode of PBP, we crystallized the Dictyostelium myosin-2 motor domain in the presence of Mg(2+)-ADP-meta-vanadate and PBP. The electron density for PBP is unambiguous and shows PBP to bind at a previously unknown allosteric site near the tip of the 50-kDa domain, at a distance of 16 A from the nucleotide binding site and 7.5 A away from the blebbistatin binding pocket.

Keywords

Adenosine Triphosphate/metabolism, Animals, Chickens, Kinetics, Models, Molecular, Myosins/antagonists & inhibitors/chemistry/drug effects/metabolism, Protein Binding, Protein Conformation, Pyrroles/pharmacology, Rats, Sensitivity and Specificity

Published Article/Book Citation

The definitive version was published in Nature structural & molecular biology, 16:1 (2009) pp.80-88. DOI:doi:10.1038/nsmb.1542.

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URL

http://ir.uiowa.edu/nursing_pubs/930