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structural changes in the protein generate a void volume around the aromatic ring to allow ring flipping to take place (Figure 41).
This discovery has implications for both protein design and structure prediction by highlighting how even small
Fig. 41: Top: Surface representation of the SH3 domain of JIP1 in three different rotameric states of Y526 corresponding to the major state, an intermediate state on the structural trajectory and the minor state. The Y526 pocket is highlighted in pink (major), blue (intermediate) and yellow (minor). These rearrangements generate a void volume around Y526, thereby lowering the transition-state energy of ring flipping and allowing the flipping of Y526. Bottom: Illustration of the protein breathing motions along the structural trajectory from the major to the minor state. A void volume is created around Y526, which allows fast ring flipping to take place. The ring flipping is occasionally interrupted by trapping of Y526 in a staggered conformation through formation of CH p interactions with L519.
changes in the delicate balance of interactions stabilising the core can lead to major changes in the protein structure. In addition, it provides a perspective on how novel biological functions can be acquired during evolution through modifications of the intricate network of interactions in the protein core, such as hydrogen bonds, CH-p and p-p
Fig. 40: Illustration of the structural changes associated with rotation of the aromatic ring of the core tyrosine residue (Y526) in the SH3 domain of the MAPK scaffold protein JIP1. The structural changes were captured by individual high-resolution crystal structures of the protein for different rotameric states of the side chain of Y526.