Abstract
Bryostatin is in clinical trials for Alzheimer’s disease, cancer, and HIV/AIDS eradication. It binds to protein kinase C competitively with diacylglycerol, the endogenous protein kinase C regulator, and plant-derived phorbol esters, but each ligand induces different activities. Determination of the structural origin for these differing activities by X-ray analysis has not succeeded due to difficulties in co-crystallizing protein kinase C with relevant ligands. More importantly, static, crystal-lattice bound complexes do not address the influence of the membrane on the structure and dynamics of membrane-associated proteins. To address this general problem, we performed long-timescale (400–500 µs aggregate) all-atom molecular dynamics simulations of protein kinase C–ligand–membrane complexes and observed that different protein kinase C activators differentially position the complex in the membrane due in part to their differing interactions with waters at the membrane inner leaf. These new findings enable new strategies for the design of simpler, more effective protein kinase C analogs and could also prove relevant to other peripheral protein complexes.
Highlights
Bryostatin is in clinical trials for Alzheimer’s disease, cancer, and HIV/AIDS eradication
While limited studies have appeared on the design of protein kinase C (PKC) modulators over the last 30 years, none has been based on multi-state dynamic structures in a membrane environment
Simulations of the PKCδ C1b domain with each one of four bound ligands (Fig. 1: bryostatin (1), phorbol 12,13-dibutyrate (PDBu, 2), a bryostatin analog (3)[32], and prostratin (4)) as well as without a ligand have been performed in the presence of a PS membrane
Summary
Bryostatin is in clinical trials for Alzheimer’s disease, cancer, and HIV/AIDS eradication. We reported the first designed PKC modulators based on computer-guided comparison of pharmacophoric features of naturally occurring PKC ligands (bryostatin, phorbol esters, DAG, ingenol, gnidimacrin, and teleocidin)[20,21,22] While these ligand comparisons have identified common pharmacophores that could contact the protein, they have not included the protein-binding domain itself. They do not address how exposed surfaces of the bound ligand might influence the depth, orientation, structure, and dynamics of the PKC–ligand complex in the membrane, issues of fundamental importance to understanding peripheral proteins. This information provides structural hypotheses required for the design and synthesis of new, simplified, and potentially superior bryostatin analogs, intensely sought after agents for research and clinical studies
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