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Updated: Apr 26, 2026
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Crystal structures of PRK1 in complex with the clinical compounds lestaurtinib and tofacitinib reveal ligand induced
Philip Chamberlain1, Silvia Delker2, Barbra Pagarigan2
1Celgene Corporation, San Diego, California, United States of America; Department of Biochemistry and Structural Biology, Celgene Corporation, San Diego, California, United States of America.
Abstract:
Protein kinase C related kinase 1 (PRK1) is a component of Rho-GTPase, androgen receptor, histone demethylase and histone deacetylase signaling pathways implicated in prostate and ovarian cancer. Herein we describe the crystal structure of PRK1 in apo form, and also in complex with a panel of literature inhibitors including the clinical candidates lestaurtinib and tofacitinib, as well as the staurosporine analog Ro-31-8220. PRK1 is a member of the AGC-kinase class, and as such exhibits the characteristic regulatory sequence at the C-terminus of the catalytic domain--the 'C-tail'. The C-tail fully encircles the catalytic domain placing a phenylalanine in the ATP-binding site. Our inhibitor structures include examples of molecules which both interact with, and displace the C-tail from the active site. This information may assist in the design of inhibitors targeting both PRK and other members of the AGC kinase family.
Insights
The crystal structure of Protein Kinase C Related Kinase 1 (PRK1) was determined. Inhibitor-bound structures reveal how molecules interact with and displace the regulatory C-tail, aiding in the design of novel kinase inhibitors.
Area of Science:
- Biochemistry
- Structural Biology
- Cancer Research
Background:
- Protein Kinase C Related Kinase 1 (PRK1) is involved in signaling pathways crucial for prostate and ovarian cancers.
- PRK1 belongs to the AGC-kinase family, characterized by a regulatory C-tail in its catalytic domain.
Purpose of the Study:
- To elucidate the crystal structure of PRK1 in its apo form.
- To characterize the structural interactions of PRK1 with various inhibitors, including clinical candidates.
- To provide insights for the development of PRK1 and other AGC kinase family inhibitors.
Main Methods:
- X-ray crystallography was employed to determine the structure of PRK1.
- Structures were solved for PRK1 in its apo state and in complex with inhibitors like lestaurtinib, tofacitinib, and Ro-31-8220.
Main Results:
- The crystal structure of apo PRK1 was determined.
- Structures revealed that the PRK1 C-tail encircles the catalytic domain, with a phenylalanine residue occupying the ATP-binding site.
- Inhibitor-bound structures demonstrated molecules that either interact with or displace the C-tail from the active site.
Conclusions:
- The determined PRK1 structures offer a detailed view of its active site and regulatory C-tail.
- Understanding inhibitor interactions with the C-tail is key for designing targeted therapies.
- These findings can guide the development of new drugs for cancers associated with PRK1 and related kinases.
