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<p>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<sup>2+</sup> 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.</p>

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Molecular basis of allosteric regulation and pharmaceutical targeting of protein kinase Cβ

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月21日

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  • 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

摘要

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 Ca2+ 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.