Crystal Structures of Anaplastic Lymphoma Kinase in Complex with ATP Competitive Inhibitors

• DOI: 10.1021/bi1005514
• Publication Date: 2010-07-13T19:53:23Z
• Authors: Roberto T. Bossi; M. Beatrice Saccardo; Elena Ardini; Maria Menichincheri; Luisa Rusconi; Paola Magnaghi; Paolo Orsini; Nilla Avanzi; Andrea Lombardi B...; Marcella Nesi; Tiziano Bandiera; Gianpaolo Fogliatto; Jay A. Bertrand
• Keywords: Protein kinase domain; Receptor Protein-Tyrosine Kinases

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine involved in the development of several human cancers and, as result, recognized target for small-molecule inhibitors treatment ALK-positive malignancies. Here, we present crystal structures unphosphorylated ALK domain complex with ATP competitive ligands PHA-E429 and NVP-TAE684. Analysis these provides valuable information concerning specific characteristics active site well giving indications about how to obtain selective inhibitors. In addition, ALK-KD-PHA-E429 structure led identification potential regulatory mechanism involving link made between short helical segment immediately following DFG motif an N-terminal two-stranded beta-sheet. Finally, mapping activating mutations associated neuroblastoma onto our may explain roles residues have activation process.