Structure of apo, unactivated insulin-like growth factor-1 receptor kinase at 1.5 Å resolution

Abstract

The crystal structure of the wild-type unactivated kinase domain (IGFRK-0P) of insulin-like growth factor-1 receptor has been reported previously at 2.7 A resolution [Munshi et al. (2002), J. Biol. Chem. 277, 38797-38802]. In order to obtain a high-resolution structure, a number of variants of IGFRK-0P were prepared and screened for crystallization. A double mutant with E1067A and E1069A substitutions within the kinase-insert region resulted in crystals that diffracted to 1.5 A resolution. Overall, the structure of the mutant IGFRK-0P is similar to that of the wild-type IGFRK-0P structure, with the exception of the previously disordered kinase-insert region in the wild type having become fixed. In addition, amino-acid residues 947-952 at the N-terminus are well defined in the mutant structure. The monomeric protein structure is folded into two lobes connected by a hinge region, with the catalytic center situated at the interface of the two lobes. Two molecules of IGFRK-0P in the asymmetric unit are associated as a dimer and two different types of dimers with their ATP-binding clefts either facing towards or away from each other are observed. The current refined model consists of a dimer and 635 water molecules.

Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models

“…Tyrosine kinase inhibitors can more indiscriminately regulate the kinase domain activity of all IGF system receptors as their primary sequence share 84% homology in the kinase domain with near complete conservation in the ATP binding pocket [31]. BMS-754807 (Supplemental Figure S1) is a potent and reversible inhibitor of IGF-1R/IR (IC 50 1.8 nM/1.7 nM), which also has more limited activity toward other kinases including Met, Aurora A/B, TrkA/B, Ron, Flt3, Lck, MK2, PKA and PKC [32, 33].…”

Autoinhibition of the insulin‐like growth factor I receptor by the juxtamembrane region

“…The juxtamembrane region amino acids beginning at N947 were resolved in a crystal structure of a mutant form of IGF1R-0P [32]. In this structure, N947 and Y950 are in a portion of the juxtamembrane region that extends away from the amino-terminal lobe of the kinase domain.…”

Polyubiquitination of Insulin-like Growth Factor I Receptor (IGF-IR) Activation Loop Promotes Antibody-induced Receptor Internalization and Down-regulation

“…The identified tryptic peptide contained two lysine residues, Lys-1138 and Lys-1141, which are located in the activation loop of the IGF-IR kinase domain; both residues interestingly are juxtaposed to the phosphorylatable tyrosine residues Tyr-1131, Tyr-1135, and Tyr-1136. Based on the crystal structures of inactive and active IGF-IR kinase domains (14,36), Lys-1138 and Lys-1141 become more surface-exposed upon phosphorylation-induced conformational changes in the activation loop (supplemental Fig. 1), likely rendering these sites more accessible to ubiquitination.…”