In this work, we execute a general synthetic strategy to access novel indolactam alkaloids, which are agonists of protein kinase C. This protocol allowed for the most efficient reported syntheses of indolactam V (ILV) stereoisomers, while also affording the large-scale production of natural product (–)-ILV. Structure–activity studies were conducted with these compounds to elucidate the elements necessary to promote PKC-mediated cellular response. EC50 measurements in leukemia and lymphoma cell lines, as well as molecular docking analyses with the PKCδ C1B domain, provided the foundation for these studies. A distinct correlation between in vitro activity and the conformation of the macrocyclic lactam ring was discovered, which can guide design efforts for therapeutics that target the PKC regulatory domain.
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Hypothesis: Unifying model of domain architecture for conventional and novel protein kinase C isozymes
Protein kinase C (PKC) family members are multi‐domain proteins whose function is exquisitely tuned by interdomain interactions that control the spatiotemporal dynamics of their signaling. Despite extensive mechanistic studies on this family of enzymes, no structure of a full‐length enzyme that includes all domains has been solved. Here, we take into account the biochemical mechanisms that control autoinhibition, the properties of each individual domain, and previous structural studies to propose a unifying model for the general architecture of PKC family members. This model shows how the C2 domains of conventional and novel PKC isozymes, which have different topologies and different positions in the primary structure, can occupy the same position in the tertiary structure of the kinase. This common architecture of conventional and novel PKC isozymes provides a framework for understanding how disease‐associated mutations impair PKC function.
more » « less- NSF-PAR ID:
- 10455161
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- IUBMB Life
- Volume:
- 72
- Issue:
- 12
- ISSN:
- 1521-6543
- Page Range / eLocation ID:
- p. 2584-2590
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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