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12-O-retinoylphorbol-13-acetate (RPA), an incomplete tumor promoter of the phorbol ester type and protein kinase C (PKC) activator, consists of two characteristic structural elements: the phorbol body and the retinoyl ester chain. Therefore, possible binding of the incomplete tumor promoter RPA to the human transport protein retinol-binding-protein (RBP) has been examined by molecular modeling methods and experimental binding studies. The calculated prediction of binding properties was primarily based on a comparative geometrical approach. It was shown that the beta-ionone-ring of RPA was not altered within the binding pocket of RBP (molecular modeling) compared to retinoic acid (X-ray crystallographic data). The torsion angle C5'-C6'-C7'-C8', determining the conformation of the RBP-beta-ionone-ring relative to the isoprene tail, is rotated by 42 degrees for RPA compared to retinol and to retinoic acid, respectively. Combining all the results from force field calculations, MD simulations and geometrical comparisons, the conclusion could be drawn that RPA should be able to bind to RBP. This interaction should be less strong than that with its natural ligand retinol or with retinoic acid. This prediction was proven experimentally. RPA was able to compete with retinoic acid for binding at RBP in human plasma. The binding properties were investigated using 3H-labeled retinoic acid in homologous and heterologous competition studies in a one-dimensional native polyacrylamide gel electrophoresis system. An approximately 2000-fold weaker binding of RPA to RBP as compared to retinoic acid was determined experimentally, confirming the prediction of the molecular modeling approach. The characteristic behaviour of RPA as an incomplete promoter, due to possible binding to PKC and RBP, is discussed.