10.1021/bi1005514.s001
Roberto T. Bossi
Roberto T.
Bossi
M. Beatrice Saccardo
M. Beatrice
Saccardo
Elena Ardini
Elena
Ardini
Maria Menichincheri
Maria
Menichincheri
Luisa Rusconi
Luisa
Rusconi
Paola Magnaghi
Paola
Magnaghi
Paolo Orsini
Paolo
Orsini
Nilla Avanzi
Nilla
Avanzi
Andrea Lombardi Borgia
Andrea Lombardi
Borgia
Marcella Nesi
Marcella
Nesi
Tiziano Bandiera
Tiziano
Bandiera
Gianpaolo Fogliatto
Gianpaolo
Fogliatto
Jay A. Bertrand
Jay A.
Bertrand
Crystal Structures of Anaplastic Lymphoma Kinase in Complex with ATP Competitive Inhibitors
American Chemical Society
2010
ALK kinase domain
ATP
helical segment
crystal structures
InhibitorsAnaplastic lymphoma kinase
DFG motif
Anaplastic Lymphoma Kinase
ALK inhibitors
receptor tyrosine kinase
activation process
crystal Structures
2010-08-17 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Crystal_Structures_of_Anaplastic_Lymphoma_Kinase_in_Complex_with_ATP_Competitive_Inhibitors/2742238
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.