Crystal structure of bisphosphorylated IGF-1 receptor kinase: insight into domain movements upon kinase activation.
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 A 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.
Pautsch
A
A
Boehringer Ingelheim Pharma KG Deutschland, Birkendorferstrasse 65, D-88400 Biberach, Germany. alexander.pautsch@bc.boehringer-ingelheim.com
Zoephel
A
A
Ahorn
H
H
Spevak
W
W
Hauptmann
R
R
Nar
H
H
D000266:Adenylyl Imidodiphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D003460:Crystallization; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity
D000266:Adenylyl Imidodiphosphate; D017526:Receptor, IGF Type 1