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This invention is a self-assembling two-dimensional (2D) crystal lattice formed by surface layer (S-layer) proteins bound to modified, water-soluble GPCR variants. Here, fusion domains have been attached to the C-terminus of S-layer peptides. To avoid the use of detergents to confer water-solubility to the GPCR, the GPCR protein of interest is altered such that all hydrophobic amino acid residues found in the 7 α-helical transmembrane domains of the protein are replaced with hydrophilic residues. The inventors have created a system that replaces distinct hydrophobic residues with hydrophilic residues of a similar size to maintain GPCR structure and function. For example, the hydrophobic phenylalanine residue contains a benzene ring, which can be replaced by tyrosine, which contains a phenol group. Phenol groups are benzene rings which have been modified with a hydroxyl group, thus conferring hydrophilicity without significantly altering the size of the residue. Therefore, this amino acid replacement confers increased water-solubility without impacting protein structure.

These water-soluble variant GPCRs are fused to a binding moiety at the C-terminus. The C-terminal binding moiety of the GPCR has binding affinity for the S-layer protein fusion domain, which allows the S-layer fusion protein and the modified GPCR to associate. The S-layer fusion proteins are able to self-assemble into a crystal lattice containing water-soluble GPCR variants. This crystallized complex can assemble onto bioelectronic interfaces to serve as a platform for high-throughput GPCR ligand-binding assays to uncover novel molecules that may act as GPCR agonists/antagonists.