Positions with high degree (i.e. had significant mutual information with a large number of other positions) were found to line a well defined inter-TM ligand binding cavity for class A as well as class C GPCRs.
These key TM positions, which have been identified solely on the basis of sequence analysis without any prior hypotheses or knowledge involving the biological or structural role of specific residues, are all located within the 7-TM binding cavity for classes A and C but not for class B, where experimental evidence for a common binding cavity does not exist.
For example, an extension of the cytoplasmic end of TM5, an outward tilt of TM6 resulting in a pairing of the cytoplasmic ends of TM5 and TM6, and conformational changes in the highly conserved D(E R3.50Y and NP7.50xxY motifs that form a binding cavity for the G protein.
From superposition the residues for DmGSTE6 that would generate a hydrophobic binding cavity for HNE appear to be Ser (catalytic residue); Pro, Pro, Pro (N-terminus helix 1); Ile (coil between beta strand 2 and helix 2); Phe, Ile, Arg, Leu (helix 4); Phe (C-terminus helix 7); Leu, Phe (helix 9).
Hence, the lack of a contiguous cohort of high degree positions is consistent with the absence of a clearly defined 7-TM binding cavity for class B receptors.
Moreover, our analysis confirms that the high MI hub positions in class B receptors do not possess a well-defined 7-TM binding cavity for ligands that is shared by the entire class.
In contrast to the relatively unconstrained binding cavity for the N-acyl chain, the rest of the product binding site has a more tailored fit.
Three aromatic residues form the binding cavity for methylated lysines of H3 in the chromodomain of animal HP1 and Pc [3], [20], [21], [27].
As capase-1 has no deep binding cavity for its ligands on its surface, the ligand-binding process occurs in the shallow crevice on the terminal surface of the receptor protein.
As seen in Table 4, none of the mutants drastically altered the capsaicin binding cavity for the NuoH mutants.
