Structure-Based Network Analysis of Activation Mechanisms in the ErbB Family of Receptor Tyrosine Kinases: The Regulatory Spine Residues Are Global Mediators of Structural Stability and Allosteric Interactions
Figure 3
Conformational Mobility Analysis of the EGFR-WT and EGFR-L858R Kinases.
Conformational mobility profiles of EGFR-WT are shown for the inactive Cdk/Src-IF1 form (pdb id 1XKK, left upper panel), the inactive Cdk/Src-IF2 state (pdb id 2RF9, middle upper panel) and the active conformation (pdb id 2ITX, right upper panel). Conformational mobility of EGFR-L858R is shown for the Cdk/Src-IF2 form (left lower panel) and the active conformation (right lower panel). The backbone heavy atoms (N,Cα,Cβ,C,O) were employed for the PCA computations. Conformational dynamics profiles were computed by averaging protein motions in the space of three lowest frequency modes. The color gradient from blue to red indicates the decreasing structural rigidity (or increasing conformational mobility) of the protein residues and refers to an average value over the backbone atoms in each residue. The functional kinase regions αC-helix, αC-β4-loop, and αE-helix as well as the R-spine residues are annotated and their positions are indicated by arrows. The R-spine residues are also highlighted in spheres and colored according to their degree of structural stability. Conformational mobility profiles were obtained from simulations of complete structures, where unresolved segments and disordered loops were modeled with the ModLoop server [127], [128]. These profiles were mapped onto the original crystal structures of EGFR for clarity of presentation.