Docking Study of Bryostatins to Protein Kinase C.DELTA. Cys2 Domain.

Abstract

The docking structure of bryostatin 1, a potent activator of protein kinase C (PKG), to the crystal structure of PKCδ cys2 domain was examined computationally. Prior to the docking study, possible conformers of the 20-membered ring of bryostatin 1 were searched by the high-temperature molecular dynamics calculation method. For each conformer thus identified, the most stable docking model to PKC was searched without any presumptions, covering all possible binding modes and ligand conformations, using our automatic docking program ADAM. Among the seven conformers, the conformer with a ring conformation almost identical to that in the crystal (root mean square deviation=0.187A) yielded the most stable PKC-bryostatin 1 complex. The bryostatin molecule fits well to the cone-shaped bottom of the PKC binding cavity, forming four hydrogen bonds with main chain groups. On the basis of this docking structure, the structure-activity relations of various bryostatins are well explained.