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Crystal structures of the Lyn protein tyrosine kinase domain in its apo- And inhibitor-bound state

Williams, N.K., Lucet, I.S., Klinken, S.P., Ingley, E.ORCID: 0000-0002-8112-9134 and Rossjohn, J. (2009) Crystal structures of the Lyn protein tyrosine kinase domain in its apo- And inhibitor-bound state. Journal of Biological Chemistry, 284 (1). pp. 284-291.

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The Src-family protein-tyrosine kinase (PTK) Lyn is the most important Src-family kinase in B cells, having both inhibitory and stimulatory activity that is dependent on the receptor, ligand, and developmental context of the B cell. An important role for Lyn has been reported in acute myeloid leukemia and chronic myeloid leukemia, as well as certain solid tumors. Although several Src-family inhibitors are available, the development of Lyn-specific inhibitors, or inhibitors with reduced off-target activity to Lyn, has been hampered by the lack of structural data on the Lyn kinase. Here we report the crystal structure of the non-liganded form of Lyn kinase domain, as well as in complex with three different inhibitors: the ATP analogue AMP-PNP; the pan Src kinase inhibitor PP2; and the BCR-Abl/Src-family inhibitor Dasatinib. The Lyn kinase domain was determined in its "active" conformation, but in the unphospho-rylated state. All three inhibitors are bound at the ATP-binding site, with PP2 and Dasatinib extending into a hydrophobic pocket deep in the substrate cleft, thereby providing a basis for the Src-specific inhibition. Analysis of sequence and structural differences around the active site region of the Src-family PTKs were evident. Accordingly, our data provide valuable information for the further development of therapeutics targeting Lyn and the important Src-family of kinases.

Item Type: Journal Article
Publisher: American Society for Biochemistry and Molecular Biology Inc.
Copyright: © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.
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