A structural rationale for selective stabilization of anti-tumor interactions of 14-3-3 proteins by cotylenin A.
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.
Ottmann
Christian
C
Chemical Genomics Centre, Max Planck Society, Dortmund, Germany. christian.ottmann@cgc.mpg.de
Weyand
Michael
M
Sassa
Takeshi
T
Inoue
Takatsugu
T
Kato
Nobuo
N
Wittinghofer
Alfred
A
Oecking
Claudia
C
D048948:14-3-3 Proteins / Q000737:chemistry* / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D002151:Calorimetry; D018360:Crystallography, X-Ray; D004224:Diterpenes / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D006027:Glycosides / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010748:Phosphopeptides / Q000737:chemistry; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D017433:Protein Structure, Secondary; D006180:Proton-Translocating ATPases / Q000737:chemistry; D013329:Structure-Activity Relationship; D014026:Nicotiana / Q000378:metabolism*
D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D004224:Diterpenes; D006027:Glycosides; D010748:Phosphopeptides; C423222:cotylenin A; C007808:fusicoccin; D006180:Proton-Translocating ATPases