Molecular basis of allosteric regulation and pharmaceutical targeting of protein kinase Cβ
- Anh T. Q. Cong
- Taylor L. Witter
- Elizabeth S. Bruinsma
- Sayantani Sarkar Bhattacharya
- Swaathi Jayaraman
- Samuel R. Wyatt
- Jasper K. Solverson
- Maria B. Dugan
- Jasmina Paluncic
- Mary J. Kuffel
- Julia R. Alvey
- Huy V. Huynh
- Xinyan Wu
- Alan P. Fields
- Akhilesh Pandey
- John R. Hawse
- Matthew P. Goetz
- Matthew J. Schellenberg
2026-05-21
Protein kinase C (PKC) isozymes are ubiquitous kinases that direct diverse cellular pathways and are important drug targets for the treatment of cancer and neurological diseases. PKCs are auto-regulating enzymes governed by phospholipid and Ca 2+ signals via a mechanism that has remained enigmatic due to a paucity of structural information. Herein we present a series of structures of the full-length human PKCβI and PKCβII isozymes. These structures reveal the molecular basis by which PKCs maintain an auto-inhibited state, convert to a defined and ordered active conformation via a “lipid-lever” mechanism of allosteric activation, and how isoform-specific differences alter their allosteric regulatory mechanisms. We show that endoxifen, a recently identified PKCβI inhibitor, can alter the allosteric regulatory mechanism of PKCβI, providing a proof of concept for allosteric regulators of PKCs. Collectively, our data describe a foundational molecular model of second messenger-mediated allosteric regulation of PKCs that underpins PKC function, misregulation, and mechanisms of inhibition.