Chivosazole A Modulates Protein Protein Interactions of Actin

Wang, Shuaijun; Gegenfurtner, Florian A.; Crevenna, Alvaro H.; Ziegenhain, Christoph; Kliesmete, Zane; Enard, Wolfgang; Müller, Rolf; Vollmar, Angelika M.; Schneider, Sabine und Zahler, Stefan (2019): Chivosazole A Modulates Protein Protein Interactions of Actin. In: Journal of Natural Products, Bd. 82, Nr. 7: S. 1961-1970

Abstract

Actin is a protein of central importance for many cellular key processes. It is regulated by local interactions with a large number of actin binding proteins (ABPs). Various compounds are known to either increase or decrease the polymerization dynamics of actin. However, no actin binding compound has been developed for clinical applications yet because of selectivity issues. We provide a crystal structure of the natural product chivosazole A (ChivoA) bound to actin and show that in addition to inhibiting nucleation, polymerization, and severing of F-actin filaments it selectively modulates binding of ABPs to G-actin: Although unphysiological actin dimers are induced by ChivoA, interaction with gelsolin, profilin, cofilin, and thymosin-beta 4 is inhibited. Moreover, ChivoA causes transcriptional effects differing from latrunculin B, an actin binder with a different binding site. Our data show that ChivoA and related compounds could serve as scaffolds for the development of actin binding molecules selectively targeting specific actin functions.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Chemie und Pharmazie > Department für Pharmazie - Zentrum für Pharmaforschung ; Biologie > Department Biologie II
• Themengebiete: 500 Naturwissenschaften und Mathematik > 540 Chemie ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften; Biologie
• ISSN: 0163-3864
• Sprache: Englisch