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High-resolution crystal structure of human Mapkap kinase 3 in complex with a high affinity ligand

DOI: 10.1002/pro.294 DOI Help
PMID: 19937655 PMID Help

Authors: Robert Cheng (Evotec (UK) Ltd) , B Felicetti (Evotec (UK) Ltd) , S Palan (Evotec (UK) Ltd) , I Toogood-johnson (Evotec (UK) Ltd) , C Scheich (Evotec AG) , M Whittaker (Evotec (UK) Ltd) , T Hesterkamp (Evotec AG) , John Barker (Evotec (UK) Ltd)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Protein Science , VOL 19 (1) , PAGES 168-173

State: Published (Approved)
Published: January 2010

Abstract: The Mapkap kinases 2 and 3 (MK2 and MK3) have been implicated in intracellular signaling pathways leading to the production of the pro-inflammatory cytokine tumor necrosis factor alpha. MK2 has been pursued by the biopharmaceutical industry for many years for the development of a small molecule anti-inflammatory treatment and drug-like inhibitors have been described. The development of some of these compounds, however, has been slowed by the absence of a high-resolution crystal structure of MK2. Herein we present a high-resolution (1.9 angstrom) crystal structure of the highly homologous MK3 in complex with a pharmaceutical lead compound. While all of the canonical features of Ser/Thr kinases in general and MK2 in particular are recapitulated in MK3, the detailed analysis of the binding interaction of the drug-like ligand within the adenine binding pocket allows relevant conclusions to be drawn for the further design of potent and selective drug candidates.

Journal Keywords: Crystallography; Humans; Intracellular; Ligands; Models; Molecular; Protein; Protein-Serine-Threonine; Recombinant Fusion Proteins

Subject Areas: Biology and Bio-materials

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Added On: 01/02/2010 15:51

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