Transmembrane proteins are challenging crystallization targets. Their ample hydrophobic surfaces create the need for restricted buffer conditions and undermine specific protein-to-protein interactions that lead to lattice formation. Cocrystallization proteins, such as antibodies, have been employed in the past to help solubilize the target protein, mediate lattice formation, and increase the chances of quality crystallization. In search of a new ligand scaffold to expand the cocrystallization ligand toolbox, we used the random non-standard peptide integrated discovery (RaPID) system to identify high-affinity, target-specific cyclic peptides and evaluated their efficacy as cocrystallization ligands. Pyrococcus furiosus multidrug and toxic compound extrusion (PfMATE) transporter was used as a model protein in our proof-of–concept experiment demonstrating the efficacy of cyclic peptides as ligands in cocrystallization. Not only does PfMATE have a copious amount of hydrophobic surface but is also proposed to be highly dynamic according to its putative proton-driven antiporter mechanism. Therefore, even highly purified samples of PfMATE could exist as a heterogeneous mixture of protein in various conformational states. The cyclic peptides identified by the RaPID system did facilitate crystallization and structure elucidation to 2.5-3.0 angstrom resolutions, but not by mediating lattice formation.1 The 17-residue macrocyclic peptide, MaL6, was found to bind to the cleft on the extracellular side between the N-terminal and C-terminal lobes. Lariat-shaped peptides MaD3S and MaD5, bearing identical 7-residue minicycle heads, were found in the substrate-binding pocket of PfMATE. Both methods of binding appear to lock PfMATE into the outward-facing conformation. Additionally, it was found that the one of the transmembrane helices, TM1, interconverted between a kinked and a straight state as part of the drug extrusion mechanism. The pocket-binding peptides would also lock this helix into the straight conformation, which further increases the homogeneity of the cyclic peptide-protein mixture.