Specific hydrogen bonds with a conserved Asn residue in the BD, as well as several ordered water molecules in the partially solvent-accessible binding crevice, orient the acetamide modification.
Ser1073.36, which was shown to be important for agonist binding in both the drd1 30 and 5-HT2A receptors, 33 is directed toward the binding crevice and interacts with the backbone carbonyl of Asp1033.32.
The single binding crevice obtained by docking may allow the design and discovery of new peptidomimetics of TT-232 in the future.
The new Ser-TM5 feature was positioned deeper in the binding crevice based on projected hydrogen bond annotation points generated from the pharmacophore hits of low-energy conformers of the full D2 receptor agonists.
The orthosteric binding pocket, defined as amino acids within 3.5 Å of the corresponding agonists, is located between TM2, 3, 5, 6, and 7, whereas EC2 lines the top of the binding crevice.
The geometry of EC2 also varies significantly; both Ile184 and Asn186 point toward the binding crevice in our model, whereas they point toward TM4 in the McRobb model.
These observations suggest that binding affinity for natural ligands drove the evolution of the STING binding crevice and eventually resulted in species-specific response to a synthetic compound.
These results were mapped to the recent crystal structure of CCR5 in complex with maraviroc, showing cross-linked residues at the tip of the maraviroc binding crevice formed by EC2.
The dimer was crystallized both in an apo and in a PEG-bound form, revealing a very well defined binding crevice and some structure flexibility at the interface.
The EC2 residues Asn186 and Ile184 in drd2 are important for ligand interactions, 54 and were therefore aligned with the corresponding Thr and Phe residues in adrb2, which point downward to the binding crevice.
