A structural rationale for selective stabilization of anti-tumor interactions of 14-3-3 proteins by cotylenin A.

Abstract

Cotylenin A, a fungal metabolite originally described as a cytokinin-like bioactive substance against plants shows differentiation-inducing and anti-tumor activity in certain human cancers. Here, we present the crystal structure of cotylenin A acting on a 14-3-3 regulatory protein complex. By comparison with the closely related, but non-anticancer agent fusicoccin A, a rationale for the activity of cotylenin A in human cancers is presented. This class of fusicoccane diterpenoids are possible general modulators of 14-3-3 protein-protein interactions. In this regard, specificities for individual 14-3-3/target protein complexes might be achieved by varying the substituent pattern of the diterpene ring system. As the different activities of fusicoccin A and cotylenin A in human cancers suggest, hydroxylation of C12 might be a sufficient determinant of structural specificity.

• Authors: Christian Ottmann, Michael Weyand, Takeshi Sassa, Takatsugu Inoue, Nobuo Kato, Alfred Wittinghofer, Claudia Oecking
• Journal: Journal of molecular biology (J Mol Biol) Vol. 386 Issue 4 Pg. 913-9 (Mar 06 2009) ISSN: 1089-8638 [Electronic] Netherlands
• PMID: 19244612 (Publication Type: Journal Article)

Chemical References

• 14-3-3 Proteins
• Antineoplastic Agents
• Diterpenes
• Glycosides
• Phosphopeptides
• cotylenin A
• fusicoccin
• Proton-Translocating ATPases

Topics

• 14-3-3 Proteins (chemistry, metabolism)
• Amino Acid Motifs
• Amino Acid Sequence
• Antineoplastic Agents (chemistry, metabolism, pharmacology)
• Calorimetry
• Crystallography, X-Ray
• Diterpenes (chemistry, metabolism, pharmacology)
• Glycosides (metabolism, pharmacology)
• Humans
• Models, Molecular
• Molecular Sequence Data
• Phosphopeptides (chemistry)
• Protein Binding (drug effects)
• Protein Multimerization (drug effects)
• Protein Stability (drug effects)
• Protein Structure, Secondary
• Proton-Translocating ATPases (chemistry)
• Structure-Activity Relationship
• Tobacco (metabolism)