6ILZ

Crystal structure of PKCiota in complex with inhibitor

Summary for 6ILZ

• Entry DOI: 10.2210/pdb6ilz/pdb
• Descriptor: Protein kinase C iota type, 2-amino-5-[3-(piperazin-1-yl)phenyl]-N-(pyridin-4-yl)pyridine-3-carboxamide (2 entities in total)
• Functional Keywords: kinase, atypical kinase, phosphorylation, inhibitor, pkciota, iota type, kinase domain, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 160917.04

Authors

Baburajendran, N.,Hill, J. (deposition date: 2018-10-21, release date: 2019-06-26, Last modification date: 2024-11-13)

Primary citation

Kwiatkowski, J.,Baburajendran, N.,Poulsen, A.,Liu, B.,Tee, D.H.Y.,Wong, Y.X.,Poh, Z.Y.,Ong, E.H.,Dinie, N.,Cherian, J.,Jansson, A.E.,Hill, J.,Keller, T.H.,Hung, A.W.
Fragment-based Discovery of a Small-Molecule Protein Kinase C-iota Inhibitor Binding Post-kinase Domain Residues.
Acs Med.Chem.Lett., 10:318-323, 2019

PubMed Abstract: The atypical protein kinase C-iota (PKC-ι) enzyme is implicated in various cancers and has been put forward as an attractive target for developing anticancer therapy. A high concentration biochemical screen identified pyridine fragment weakly inhibiting PKC-ι with IC = 424 μM. Driven by structure-activity relationships and guided by docking hypothesis, the weakly bound fragment was eventually optimized into a potent inhibitor of PKC-ι (IC= 270 nM). Through the course of the optimization, an intermediate compound was crystallized with the protein, and careful analysis of the X-ray crystal structure revealed a unique binding mode involving the post-kinase domain (C-terminal tail) of PKC-ι.

PubMed: 30891133
DOI: 10.1021/acsmedchemlett.8b00546

Experimental method

X-RAY DIFFRACTION (3.261 Å)