Crystal structures of ASK1‐inhibtor complexes provide a platform for structure‐based drug design

• Published in: Protein science Vol. 22; no. 8; pp. 1071 - 1077
• Main Authors: Singh, Onkar, Shillings, Anthony, Craggs, Peter, Wall, Ian, Rowland, Paul, Skarzynski, Tadeusz, Hobbs, Clare I., Hardwick, Phil, Tanner, Rob, Blunt, Michelle, Witty, David R., Smith, Kathrine J.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.08.2013; Blackwell Publishing Ltd
• Subjects: apoptosis signal regulating kinase 1; ASK1; Binding Sites; Cardiovascular Diseases - drug therapy; Crystallography, X-Ray; Drug Design; Humans; Kinases; Ligands; MAP Kinase Kinase Kinase 5 - antagonists & inhibitors; MAP Kinase Kinase Kinase 5 - chemistry; MAP Kinase Kinase Kinase 5 - genetics; MAP Kinase Kinase Kinase 5 - metabolism; Neoplasms - drug therapy; Neurodegenerative Diseases - drug therapy; Sf9 Cells; Signal Transduction; Staurosporine - chemistry; structure base drug design; ASK1; apoptosis signal regulating kinase 1; structure base drug design
• ISSN: 0961-8368; 1469-896X
• DOI: 10.1002/pro.2298

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.