title: High-resolution crystal structure of human Mapkap kinase 3 in complex with a high affinity ligand.
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.
authors: Evotec (UK) Ltd, 114 Milton Park, Abingdon, Oxfordshire OX14 4SA, United Kingdom.
authors: Robert
authors: R
authors: Cheng
authors: Brunella
authors: B
authors: Felicetti
authors: Shilpa
authors: S
authors: Palan
authors: Ian
authors: I
authors: Toogood-Johnson
authors: Christoph
authors: C
authors: Scheich
authors: John
authors: J
authors: Barker
authors: Mark
authors: M
authors: Whittaker
authors: Thomas
authors: T
authors: Hesterkamp
mesh_terms: D020134:Catalytic Domain; D003461:Crystallography / Q000379:methods*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D017346:Protein Serine-Threonine Kinases; D011993:Recombinant Fusion Proteins; D000099190:MAP-Kinase-Activated Kinase 2; C098416:MAP-kinase-activated kinase 3