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

Chamberlain P, Delker S, Pagarigan B, Mahmoudi A, Jackson P, Abbasian M, Muir J, Raheja N, Cathers B - PLoS ONE (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Celgene 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.

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Related in: MedlinePlus

Comparison of PRK1 to PKA.The structure of PRK1 is shown colored from blue to red (N- to C- terminus); PKA (1BKX) is shown in grey. Sites of phosphorylation (PRK1 residues S922 and T780, PKA residue S338) are shown as sticks, as is active site tether residue F910 (PRK1). The structures show good alignment, with a divergence in the conformation of the C-tail as it passes over the N-lobe.
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pone-0103638-g002: Comparison of PRK1 to PKA.The structure of PRK1 is shown colored from blue to red (N- to C- terminus); PKA (1BKX) is shown in grey. Sites of phosphorylation (PRK1 residues S922 and T780, PKA residue S338) are shown as sticks, as is active site tether residue F910 (PRK1). The structures show good alignment, with a divergence in the conformation of the C-tail as it passes over the N-lobe.

Mentions: The structure of apo PRK1 has been solved to 2 Å resolution (Table 1). In the apo structure, the entire C-terminal region of the gene containing the catalytic domain and C-tail is fully defined in the electron density. Two phosphorylation sites were determined to be present by mass spectral (MS) analysis (Data not shown), and both of these are clearly visible in the structure, at residues Thr780 in the activation loop and Ser922 in the Turn-motif (Figure 2). Structural alignment with PKA yields a 1.8 Å RMSD over 270 aligned residues (PKA coordinates 1BKX, Figure 2).


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

Chamberlain P, Delker S, Pagarigan B, Mahmoudi A, Jackson P, Abbasian M, Muir J, Raheja N, Cathers B - PLoS ONE (2014)

Comparison of PRK1 to PKA.The structure of PRK1 is shown colored from blue to red (N- to C- terminus); PKA (1BKX) is shown in grey. Sites of phosphorylation (PRK1 residues S922 and T780, PKA residue S338) are shown as sticks, as is active site tether residue F910 (PRK1). The structures show good alignment, with a divergence in the conformation of the C-tail as it passes over the N-lobe.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128815&req=5

pone-0103638-g002: Comparison of PRK1 to PKA.The structure of PRK1 is shown colored from blue to red (N- to C- terminus); PKA (1BKX) is shown in grey. Sites of phosphorylation (PRK1 residues S922 and T780, PKA residue S338) are shown as sticks, as is active site tether residue F910 (PRK1). The structures show good alignment, with a divergence in the conformation of the C-tail as it passes over the N-lobe.
Mentions: The structure of apo PRK1 has been solved to 2 Å resolution (Table 1). In the apo structure, the entire C-terminal region of the gene containing the catalytic domain and C-tail is fully defined in the electron density. Two phosphorylation sites were determined to be present by mass spectral (MS) analysis (Data not shown), and both of these are clearly visible in the structure, at residues Thr780 in the activation loop and Ser922 in the Turn-motif (Figure 2). Structural alignment with PKA yields a 1.8 Å RMSD over 270 aligned residues (PKA coordinates 1BKX, Figure 2).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Celgene 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.

Show MeSH
Related in: MedlinePlus