Crystal Structure of Bisphosphorylated IGF-1 Receptor Kinase: Insight into Domain Movements upon Kinase Activation

• Published in: Structure (London) Vol. 9; no. 10; pp. 955 - 965
• Main Authors: Pautsch, Alexander, Zoephel, Andreas, Ahorn, Horst, Spevak, Walter, Hauptmann, Rudolf, Nar, Herbert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2001
• Subjects: Adenylyl Imidodiphosphate - metabolism; Amino Acid Sequence; Binding Sites; cancer; Catalytic Domain; crystal structure; Crystallization; Crystallography, X-Ray; Enzyme Activation; growth-factor receptor; Humans; IGF-1; Molecular Sequence Data; Phosphorylation; Protein Binding; Protein Conformation; Protein Structure, Tertiary; protein tyrosine kinase; Receptor, IGF Type 1 - biosynthesis; Receptor, IGF Type 1 - chemistry; Receptor, IGF Type 1 - metabolism; Substrate Specificity; crystal structure; growth-factor receptor; cancer; IGF-1; protein tyrosine kinase
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/S0969-2126(01)00655-4

Background: The insulin-like growth-factor-1 (IGF-1) receptor, which is widely expressed in cells that have undergone oncogenic transformation, is emerging as a novel target in cancer therapy. IGF-1-induced receptor activation results in autophosphorylation of cytoplasmic kinase domains and enhances their capability to phosphorylate downstream substrates. Structures of the homologous insulin receptor kinase (IRK) exist in an open, unphosphorylated form and a closed, trisphosphorylated form. Results: We have determined the 2.1 Å crystal structure of the IGF-1 receptor protein tyrosine kinase domain phosphorylated at two tyrosine residues within the activation loop (IGF-1RK2P) and bound to an ATP analog. The ligand is not in a conformation compatible with phosphoryl transfer, and the activation loop is partially disordered. Compared to the homologous insulin receptor kinase, IGF-1RK2P is trapped in a half-closed, previously unobserved conformation. Observed domain movements can be dissected into two orthogonal rotational components. Conclusions: Conformational changes upon kinase activation are triggered by the degree of phosphorylation and are crucially dependent on the conformation of the proximal end of the kinase activation loop. This IGF-1RK structure will provide a molecular basis for the design of selective antioncogenic therapeutic agents.