Crystal structures of PRK1 in complex with the clinical compounds lestaurtinib and tofacitinib reveal ligand induced conformational changes

Philip Chamberlain; Silvia Delker; Barbra Pagarigan; Afshin Mahmoudi; Pilgrim Jackson; Mahan Abbasian; Jeff Muir; Neil Raheja; Brian Cathers

doi:10.1371/journal.pone.0103638

Crystal structures of PRK1 in complex with the clinical compounds lestaurtinib and tofacitinib reveal ligand induced conformational changes

PLoS One. 2014 Aug 11;9(8):e103638. doi: 10.1371/journal.pone.0103638. eCollection 2014.

Authors

Philip Chamberlain¹, Silvia Delker², Barbra Pagarigan², Afshin Mahmoudi², Pilgrim Jackson², Mahan Abbasian², Jeff Muir², Neil Raheja², Brian Cathers²

Affiliations

¹ Celgene Corporation, San Diego, California, United States of America; Department of Biochemistry and Structural Biology, Celgene Corporation, San Diego, California, United States of America.
² 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoenzymes / antagonists & inhibitors
Apoenzymes / chemistry
Apoenzymes / metabolism
Carbazoles / metabolism*
Carbazoles / pharmacology*
Crystallography, X-Ray
Furans
Humans
Ligands
Piperidines / metabolism*
Piperidines / pharmacology*
Protein Conformation / drug effects
Protein Kinase C / antagonists & inhibitors
Protein Kinase C / chemistry*
Protein Kinase C / metabolism*
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology
Pyrimidines / metabolism*
Pyrimidines / pharmacology*
Pyrroles / metabolism*
Pyrroles / pharmacology*

Substances

Apoenzymes
Carbazoles
Furans
Ligands
Piperidines
Protein Kinase Inhibitors
Pyrimidines
Pyrroles
tofacitinib
lestaurtinib
protein kinase N
Protein Kinase C

Associated data

PDB/4OTD
PDB/4OTG
PDB/4OTH
PDB/4OTI

Grants and funding

This work was funded by Celgene. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.