Journal
JOURNAL OF NATURAL PRODUCTS
Volume 82, Issue 7, Pages 1961-1970Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jnatprod.9b00335
Keywords
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Funding
- Chinese Scholarship Council
- German Research Foundation (DFG) [SFB1032, SCHN1273/6-1, CIPSM, FOR1406]
- Project (Microbiologia Molecular, Estrutural e Celular) - FEDER funds through COMPETE2020 - Programa Operacional Competitividade e Internacionalizacao (POCI) [LISBOA-01-0145-FEDER-007660]
- national funds through FCT - Fundacao para a Ciencia e a Tecnologia
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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.
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