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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.

SUBMITTER: Singh O

PROVIDER: S-EPMC3832043 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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

Singh Onkar O Shillings Anthony A Craggs Peter P Wall Ian I Rowland Paul P Skarzynski Tadeusz T Hobbs Clare I CI Hardwick Phil P Tanner Rob R Blunt Michelle M Witty David R DR Smith Kathrine J KJ

Protein science : a publication of the Protein Society 20130703 8

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 rang ...[more]

PMID: 23776076

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