When Dr. Matthew Schellenberg stared at the first clear image of the full-length PKCβ protein on his screen in Rochester, he was looking at a structure that had eluded scientists for nearly 40 years — a molecular puzzle first identified in the 1980s and now, finally, solved. At Mayo Clinic, Schellenberg and his team have revealed the detailed architecture of protein kinase C beta (PKCβ), a protein deeply involved in cell signaling and long implicated in cancers and neurological disorders like Alzheimer’s. Their breakthrough, published in Nature Communications, not only unveils how PKCβ is regulated but also shows how the breast cancer drug endoxifen interacts with it in a way that could reshape precision medicine.
PKC proteins act as cellular switches, controlling processes from growth to survival. With 10 different isoforms in the human body, their roles are complex — some promote disease, others protect against it. But without knowing their exact structures, designing targeted therapies has been like trying to pick a lock without seeing the keyhole. The Mayo team overcame decades of technical hurdles by producing human PKCβ1 and PKCβ2 in human cells, rather than the traditional insect cell systems, yielding a more accurate, high-resolution view of the protein’s natural form.
The images revealed a striking mechanism: lipid membranes inside cells act as molecular levers, flipping PKCβ from a closed, inactive state into an open, active configuration. But even more surprising was what happened with endoxifen. Rather than blocking the enzyme’s active site, the drug works allosterically — binding elsewhere and stabilizing PKCβ in the membrane, which ultimately leads to its degradation. This is not how earlier PKC inhibitors functioned, and it may explain why endoxifen shows stronger biological effects in clinical settings.
“This mechanism is fundamentally different from previous PKC inhibitors that have been tested over the years,” says Dr. Matthew Goetz, a medical oncologist at Mayo Clinic Comprehensive Cancer Center and study co-author. “That distinction may help explain why endoxifen shows biological effects that earlier compounds did not.” The discovery opens doors to designing drugs that can selectively target specific PKC isoforms in specific disease contexts, minimizing side effects and maximizing efficacy.
Today, Mayo researchers are studying endoxifen in premenopausal women with estrogen receptor-positive breast cancer, probing whether its action on PKCβ contributes to its therapeutic benefit. With the full structure now known, the team is planning to extend their work to the other nine PKC family members, building a comprehensive map of this critical protein family. For a field that has waited 40 years for clarity, the path forward has never been brighter.