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Sci Rep. 2019 Jul 5;9(1):9731. doi: 10.1038/s41598-019-46282-w.

Actin stabilizing compounds show specific biological effects due to their binding mode.

Author information

1
Department of Pharmacy, Ludwig-Maximilians-Universität, 81377, Munich, Germany.
2
Department of Chemistry, Center for Nanoscience (CeNS), Center for Integrated Protein Science Munich, (CIPSM) and Nanosystems Initiative Munich (NIM), Ludwig-Maximilians-Universität, 81377, Munich, Germany.
3
Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Nova de Lisboa, Portugal.
4
Center for Integrated Protein Science at the Department for Biosciences, Technical University Munich, 85354, Freising, Germany.
5
Institute for Organic Chemistry, Saarland University, 66123, Saarbrücken, Germany.
6
Department Biology II, Anthropology and Human Genomics, Ludwig-Maximilians-University, 82152, Martinsried, Germany.
7
Department of Pharmacy, Ludwig-Maximilians-Universität, 81377, Munich, Germany. Stefan.zahler@cup.uni-muenchen.de.

Abstract

Actin binding compounds are widely used tools in cell biology. We compare the biological and biochemical effects of miuraenamide A and jasplakinolide, a structurally related prototypic actin stabilizer. Though both compounds have similar effects on cytoskeletal morphology and proliferation, they affect migration and transcription in a distinctive manner, as shown by a transcriptome approach in endothelial cells. In vitro, miuraenamide A acts as an actin nucleating, F-actin polymerizing and stabilizing compound, just like described for jasplakinolide. However, in contrast to jasplakinolide, miuraenamide A competes with cofilin, but not gelsolin or Arp2/3 for binding to F-actin. We propose a binding mode of miuraenamide A, explaining both its similarities and its differences to jasplakinolide. Molecular dynamics simulations suggest that the bromophenol group of miurenamide A interacts with residues Tyr133, Tyr143, and Phe352 of actin. This shifts the D-loop of the neighboring actin, creating tighter packing of the monomers, and occluding the binding site of cofilin. Since relatively small changes in the molecular structure give rise to this selectivity, actin binding compounds surprisingly are promising scaffolds for creating actin binders with specific functionality instead of just "stabilizers".

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