High-resolution crystal structure of human Mapkap kinase 3 in complex with a high affinity ligand.
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Cheng R, Felicetti B, Palan S, Toogood-Johnson I, Scheich C, Barker J, Whittaker M, Hesterkamp T
High-resolution crystal structure of human Mapkap kinase 3 in complex with a high affinity ligand.
Protein Sci. 2010 Jan;19(1):168-73. doi: 10.1002/pro.294.
- PubMed ID
- 19937655 [ View in PubMed]
- 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 A) 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.