4OTI

Crystal Structure of PRK1 Catalytic Domain in Complex with Tofacitinib

Summary for 4OTI

• Entry DOI: 10.2210/pdb4oti/pdb
• Related: 4OTD 4OTG 4OTH
• Descriptor: Serine/threonine-protein kinase N1, 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile (3 entities in total)
• Functional Keywords: prk1, pkn1, protein kinase c related kinase 1, kinase, protein kinase, atp binding, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : Q16512
• Total number of polymer chains: 1
• Total formula weight: 38653.87

Authors

Chamberlain, P.P.,Delker, S.,Pagarigan, B.,Mahmoudi, A.,Jackson, P.,Abbassian, M.,Muir, J.,Raheja, N.,Cathers, B. (deposition date: 2014-02-13, release date: 2014-08-27, Last modification date: 2024-10-16)

Primary citation

Chamberlain, P.,Delker, S.,Pagarigan, B.,Mahmoudi, A.,Jackson, P.,Abbasian, M.,Muir, J.,Raheja, N.,Cathers, B.
Crystal Structures of PRK1 in Complex with the Clinical Compounds Lestaurtinib and Tofacitinib Reveal Ligand Induced Conformational Changes.
Plos One, 9:e103638-e103638, 2014

PubMed 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.

PubMed: 25111382
DOI: 10.1371/journal.pone.0103638

Experimental method

X-RAY DIFFRACTION (1.93 Å)