7UP4

Crystal structure of C-terminal Domain of MSK1 in complex with covalently bound pyrrolopyrimidine compound 20 (co-crystal)

Summary for 7UP4

• Entry DOI: 10.2210/pdb7up4/pdb
• Descriptor: Ribosomal protein S6 kinase alpha-5, (5M)-5-(2,5-dichloropyrimidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine (3 entities in total)
• Functional Keywords: msk1, c-terminal domain, protein kinase, transferase, phosphorylation
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 69869.79

Authors

Yano, J.K.,Abendroth, J.,Hall, A. (deposition date: 2022-04-14, release date: 2022-07-06, Last modification date: 2024-10-30)

Primary citation

Hall, A.,Abendroth, J.,Bolejack, M.J.,Ceska, T.,Dell'Aiera, S.,Ellis, V.,Fox 3rd, D.,Francois, C.,Muruthi, M.M.,Prevel, C.,Poullennec, K.,Romanov, S.,Valade, A.,Vanbellinghen, A.,Yano, J.,Geraerts, M.
Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1.
Acs Med.Chem.Lett., 13:1099-1108, 2022

PubMed Abstract: We describe the identification and characterization of a series of covalent inhibitors of the C-terminal kinase domain (CTKD) of MSK1. The initial hit was identified via a high-throughput screening and represents a rare example of a covalent inhibitor which acts via an SAr reaction of a 2,5-dichloropyrimidine with a cysteine residue (Cys440). The covalent mechanism of action was supported by biochemical experiments and was confirmed by mass spectrometry. Ultimately, the displacement of the 2-chloro moiety was confirmed by crystallization of an inhibitor with the CTKD. We also disclose the crystal structures of three compounds from this series bound to the CTKD of MSK1, in addition to the crystal structures of two unrelated RSK2 covalent inhibitors bound to the CTKD of MSK1.

PubMed: 35859861
DOI: 10.1021/acsmedchemlett.2c00134

Experimental method

X-RAY DIFFRACTION (3 Å)