Figure 1. Structures of the major G and minor E states of L99A T4L and the hidden state hypothesis.

The X-ray structure of the G state ($G_{Xray}$; PDB ID code 3DMV) has a large internal cavity within the core of the C-terminal domain that is able to bind hydrophobic ligands. The structure of the E state ($E_{ROSETTA}$; PDB ID code 2LC9) was previously determined by CS-ROSETTA using chemical shifts. The G and E states are overall similar, apart from the region surrounding the internal cavity. Comparison of the two structures revealed two remarkable conformational changes from G to E: helix F (denoted as $H_F$) rotates and fuses with helix G ($H_G$) into a longer helix, and the side chain of phenylalanine at position 114 ($F_{114}$) rotates so as to occupy part of the cavity. As the cavity is inaccessible in both the $G_{Xray}$ and $E_{ROSETTA}$ structures it has been hypothesized that ligand entry occurs via a third ‘cavity open’ state (Merski et al., 2015).

DOI: http://dx.doi.org/10.7554/eLife.17505.003