title: Crystal structures of anaplastic lymphoma kinase in complex with ATP competitive inhibitors.
abstract: 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 beta-sheet. Finally, mapping of the activating mutations associated with neuroblastoma onto our structures may explain the roles these residues have in the activation process.
authors.affiliation: Nerviano Medical Sciences S.r.l., Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Roberto T
authors.initials: RT
authors.lastname: Bossi
authors.forename: M Beatrice
authors.initials: MB
authors.lastname: Saccardo
authors.forename: Elena
authors.initials: E
authors.lastname: Ardini
authors.forename: Maria
authors.initials: M
authors.lastname: Menichincheri
authors.forename: Luisa
authors.initials: L
authors.lastname: Rusconi
authors.forename: Paola
authors.initials: P
authors.lastname: Magnaghi
authors.forename: Paolo
authors.initials: P
authors.lastname: Orsini
authors.forename: Nilla
authors.initials: N
authors.lastname: Avanzi
authors.forename: Andrea Lombardi
authors.initials: AL
authors.lastname: Borgia
authors.forename: Marcella
authors.initials: M
authors.lastname: Nesi
authors.forename: Tiziano
authors.initials: T
authors.lastname: Bandiera
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Fogliatto
authors.forename: Jay A
authors.initials: JA
authors.lastname: Bertrand
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry*; D020794:Receptor Protein-Tyrosine Kinases; D018411:Spodoptera
chemical_list: D004791:Enzyme Inhibitors; C516714:NVP-TAE684; D011743:Pyrimidines; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases