2ZV8

Lyn Tyrosine Kinase Domain-AMP-PNP complex

Summary for 2ZV8

• Entry DOI: 10.2210/pdb2zv8/pdb
• Related: 2ZV7 2ZV9 2ZVA
• Descriptor: Tyrosine-protein kinase Lyn, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER (3 entities in total)
• Functional Keywords: lyn kinase amppnp, alternative splicing, atp-binding, kinase, lipoprotein, myristate, nucleotide-binding, palmitate, phosphoprotein, proto-oncogene, sh2 domain, sh3 domain, transferase, tyrosine-protein kinase
• Biological source: Mus musculus (mouse)
• Cellular location: Cell membrane (By similarity): P25911
• Total number of polymer chains: 1
• Total formula weight: 32316.83

Authors

Williams, N.K.,Rossjohn, J. (deposition date: 2008-11-04, release date: 2008-11-11, Last modification date: 2023-11-01)

Primary citation

Williams, N.K.,Lucet, I.S.,Klinken, S.P.,Ingley, E.,Rossjohn, J.
Crystal Structures of the Lyn Protein Tyrosine Kinase Domain in Its Apo- and Inhibitor-bound State
J.Biol.Chem., 284:284-291, 2009

PubMed Abstract: 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 unphosphorylated 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.

PubMed: 18984583
DOI: 10.1074/jbc.M807850200

Experimental method

X-RAY DIFFRACTION (2.7 Å)