title: Crystal structures of ASK1-inhibtor complexes provide a platform for structure-based drug design.
abstract: ASK1, a member of the MAPK Kinase Kinase family of proteins has been shown to play a key role in cancer, neurodegeneration and cardiovascular diseases and is emerging as a possible drug target. Here we describe a 'replacement-soaking' method that has enabled the high-throughput X-ray structure determination of ASK1/ligand complexes. Comparison of the X-ray structures of five ASK1/ligand complexes from 3 different chemotypes illustrates that the ASK1 ATP binding site is able to accommodate a range of chemical diversity and different binding modes. The replacement-soaking system is also able to tolerate some protein flexibility. This crystal system provides a robust platform for ASK1/ligand structure determination and future structure based drug design.
authors.affiliation: GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom.
authors.forename: Onkar
authors.initials: O
authors.lastname: Singh
authors.forename: Anthony
authors.initials: A
authors.lastname: Shillings
authors.forename: Peter
authors.initials: P
authors.lastname: Craggs
authors.forename: Ian
authors.initials: I
authors.lastname: Wall
authors.forename: Paul
authors.initials: P
authors.lastname: Rowland
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Skarzynski
authors.forename: Clare I
authors.initials: CI
authors.lastname: Hobbs
authors.forename: Phil
authors.initials: P
authors.lastname: Hardwick
authors.forename: Rob
authors.initials: R
authors.lastname: Tanner
authors.forename: Michelle
authors.initials: M
authors.lastname: Blunt
authors.forename: David R
authors.initials: DR
authors.lastname: Witty
authors.forename: Kathrine J
authors.initials: KJ
authors.lastname: Smith
mesh_terms: D001665:Binding Sites; D002318:Cardiovascular Diseases / Q000188:drug therapy; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008024:Ligands; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D061987:Sf9 Cells; D015398:Signal Transduction; D019311:Staurosporine / Q000737:chemistry*
chemical_list: D008024:Ligands; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D019311:Staurosporine
keywords: ASK1; apoptosis signal regulating kinase 1; structure base drug design