TY - DATA T1 - Crystal Structures of Anaplastic Lymphoma Kinase in Complex with ATP Competitive Inhibitors PY - 2010/08/17 AU - Roberto T. Bossi AU - M. Beatrice Saccardo AU - Elena Ardini AU - Maria Menichincheri AU - Luisa Rusconi AU - Paola Magnaghi AU - Paolo Orsini AU - Nilla Avanzi AU - Andrea Lombardi Borgia AU - Marcella Nesi AU - Tiziano Bandiera AU - Gianpaolo Fogliatto AU - Jay A. Bertrand UR - https://acs.figshare.com/articles/journal_contribution/Crystal_Structures_of_Anaplastic_Lymphoma_Kinase_in_Complex_with_ATP_Competitive_Inhibitors/2742238 DO - 10.1021/bi1005514.s001 L4 - https://ndownloader.figshare.com/files/4419682 KW - ALK kinase domain KW - ATP KW - helical segment KW - crystal structures KW - InhibitorsAnaplastic lymphoma kinase KW - DFG motif KW - Anaplastic Lymphoma Kinase KW - ALK inhibitors KW - receptor tyrosine kinase KW - activation process KW - crystal Structures N2 - Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in the development of several human cancers and, as a result, is a recognized target for the development of small-molecule inhibitors for the treatment of ALK-positive malignancies. Here, we present the crystal structures of the unphosphorylated human ALK kinase domain in complex with the ATP competitive ligands PHA-E429 and NVP-TAE684. Analysis of these structures provides valuable information concerning the specific characteristics of the ALK active site as well as giving indications about how to obtain selective ALK inhibitors. In addition, the ALK-KD−PHA-E429 structure led to the identification of a potential regulatory mechanism involving a link made between a short helical segment immediately following the DFG motif and an N-terminal two-stranded β-sheet. Finally, mapping of the activating mutations associated with neuroblastoma onto our structures may explain the roles these residues have in the activation process. ER -