Conservation of\nAllosteric Ligand Binding Sites in\nG‑Protein Coupled Receptors

Despite the growing number of G protein-coupled\nreceptor (GPCR)\nstructures, only 39 structures have been cocrystallized with allosteric\ninhibitors. These structures have been studied by protein mapping\nusing the FTMap server, which determines the clustering of small organic\nprobe molecules distributed on the protein surface. The method has\nfound druggable sites overlapping with the cocrystallized allosteric\nligands in 21 GPCR structures. Mapping of Alphafold2 generated models\nof these proteins confirms that the same sites can be identified without\nthe presence of bound ligands. We then mapped the 394 GPCR X-ray structures\navailable at the time of the analysis (September 2020). Results show\nthat for each of the 21 structures with bound ligands there exist\nmany other GPCRs that have a strong binding hot spot at the same location,\nsuggesting potential allosteric sites in a large variety of GPCRs.\nThese sites cluster at nine distinct locations, and each can be found\nin many different proteins. However, ligands binding at the same location\ngenerally show little or no similarity, and the amino acid residues\ninteracting with these ligands also differ. Results confirm the possibility\nof specifically targeting these sites across GPCRs for allosteric\nmodulation and help to identify the most likely binding sites among\nthe limited number of potential locations. The FTMap server is available\nfree of charge for academic and governmental use at https://ftmap.bu.edu/.