Molecular basis of allosteric regulation and pharmaceutical targeting of protein kinase Cβ
Abstract 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.
Authors
- Matthew J. Schellenberg (ORCID: https://orcid.org/0000-0001-7036-5943)
- Sayantani Sarkar Bhattacharya (ORCID: https://orcid.org/0000-0001-8971-7566)
- Taylor L. Witter (ORCID: https://orcid.org/0000-0003-3096-3011)
- Anh Cong (ORCID: https://orcid.org/0000-0001-9307-7741)
- John R. Hawse (ORCID: https://orcid.org/0000-0003-3406-470X)
- Swaathi Jayaraman (ORCID: https://orcid.org/0000-0002-5451-0052)
- Jasmina Paluncic (ORCID: https://orcid.org/0000-0003-3420-1532)
- Maria Dugan (ORCID: https://orcid.org/0000-0001-5862-6637)
- Alan P. Fields (ORCID: https://orcid.org/0000-0001-9529-0888)
- Elizabeth S. Bruinsma (ORCID: https://orcid.org/0000-0002-7938-438X)
- Julia R Alvey (ORCID: https://orcid.org/0000-0001-6549-9816)
- Mary J. Kuffel
- Huy V. Huynh (ORCID: https://orcid.org/0009-0007-9304-8087)
- Jasper K. Solverson (ORCID: https://orcid.org/0000-0001-5801-821X)
- Akhilesh Pandey (ORCID: https://orcid.org/0000-0001-9943-6127)
- Samuel R. Wyatt
- Xinyan Wu
- Matthew P. Goetz (ORCID: https://orcid.org/0000-0002-4383-270X)
Institutions
- Mayo Clinic (US)
- Manipal Academy of Higher Education (IN)
- Mayo Clinic in Arizona (US)
- Mayo Clinic in Florida (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-05-21
- DOI
- https://doi.org/10.1038/s41467-026-73413-5
- Primary Topic
- Protein Kinase Regulation and GTPase Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institutes of Health