3ZH8

A novel small molecule aPKC inhibitor

Summary for 3ZH8

• Entry DOI: 10.2210/pdb3zh8/pdb
• Descriptor: PROTEIN KINASE C IOTA TYPE, IODIDE ION, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: transferase, agc kinases, cell polarity, cell migration
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 3
• Total formula weight: 124448.51

Authors

Kjaer, S.,Purkiss, A.G.,Kostelecky, B.,Knowles, P.P.,Soriano, E.,Murray-Rust, J.,McDonald, N.Q. (deposition date: 2012-12-20, release date: 2013-02-27, Last modification date: 2024-10-16)

Primary citation

Kjaer, S.,Linch, M.,Purkiss, A.,Kostelecky, B.,Knowles, P.P.,Rosse, C.,Riou, P.,Soudy, C.,Kaye, S.,Patel, B.,Soriano, E.,Murray-Rust, J.,Barton, C.,Dillon, C.,Roffey, J.,Parker, P.J.,Mcdonald, N.Q.
Adenosine-Binding Motif Mimicry and Cellular Effects of a Thieno[2,3-D]Pyrimidine-Based Chemical Inhibitor of Atypical Protein Kinase C Isozymes.
Biochem.J., 451:329-, 2013

PubMed Abstract: The aPKC [atypical PKC (protein kinase C)] isoforms ι and ζ play crucial roles in the formation and maintenance of cell polarity and represent attractive anti-oncogenic drug targets in Ras-dependent tumours. To date, few isoform-specific chemical biology tools are available to inhibit aPKC catalytic activity. In the present paper, we describe the identification and functional characterization of potent and selective thieno[2,3-d]pyrimidine-based chemical inhibitors of aPKCs. A crystal structure of human PKCι kinase domain bound to a representative compound, CRT0066854, reveals the basis for potent and selective chemical inhibition. Furthermore, CRT0066854 displaces a crucial Asn-Phe-Asp motif that is part of the adenosine-binding pocket and engages an acidic patch used by arginine-rich PKC substrates. We show that CRT0066854 inhibits the LLGL2 (lethal giant larvae 2) phosphorylation in cell lines and exhibits phenotypic effects in a range of cell-based assays. We conclude that this compound can be used as a chemical tool to modulate aPKC activity in vitro and in vivo and may guide the search for further aPKC-selective inhibitors.

PubMed: 23418854
DOI: 10.1042/BJ20121871

Experimental method

X-RAY DIFFRACTION (2.739 Å)