Hipolito Christopher John, Nishio Kosuke, Suga Hiroaki
Department of Chemistry, Graduate School of Science, The University of Tokyo.
Yakugaku Zasshi. 2016;136(2):191-6. doi: 10.1248/yakushi.15-00229-4.
Membrane proteins allow a cell to communicate with its environment by relaying a signal or transporting a molecule through the cell membrane. Elucidation of the three-dimensional structure of a membrane protein provides a greater understanding of its function and mechanisms. Ultimately, this knowledge will enlighten researchers on how these proteins can be regulated to elicit a desired cellular response, which could lead to novel therapeutic medicine. Unfortunately, the determination of the high-resolution crystal structures of transmembrane proteins remains a challenge due to their poor solubility and high conformational flexibility. Additives and cocrystallization ligands are being used to address these problems. In vitro selected macrocyclic peptides have recently been successfully employed as cocrystallization ligands. Although originally intended as inhibitors and drug lead molecules, in vitro selected macrocyclic peptides are now showing that their pharmacodynamic properties also allow them to serve as excellent cocrystallization ligands. Structures for macrocyclic peptide-bound transporters, the multidrug and toxic compound extrusion family transporter from Pyrococcus furiosus (PfMATE) and the ABC transporter subfamily B member 1 from Cyanidioschyzon meraloe (CmABCB1), have been elucidated using X-ray crystallography. The cocrystal structures reveal that the macrocyclic peptides improve crystallization by binding in a similar manner as a small molecule or a biologic. The PfMATE-binding macrocyclic peptides MaD3S and MaD5 bind to the surfaces buried in the center channel of the transporters. Although both transporters possess a center channel and substrate-binding pocket, the CmABCB1-binding macrocyclic peptide, aCAP, binds to the outer surface of the transporter in a similar manner to a biologic.
