The Crystal Structures of the Calcium-Bound con-G and con-T[K7γ] Dimeric Peptides Demonstrate a Metal-Dependent Helix-Forming Motif

摘要

Short peptides that have the ability to form stable α-helices in solution are rare, and a number of strategies have been used to produce them, including the use of metal chelation to stabilize folding of the backbone. However, no example exists of a structurally well-defined helix stabilized exclusively through metal ion chelation. Conantokins (con)-G and -T are short peptides that are potent antagonists of N-methyl-D-aspartate receptor channels. While con-G exhibits no helicity alone, it undergoes a structural transition to a helical conformation in the presence of a variety of multivalent cations, especially Mg~(2+) and Ca~(2+). This complexation also results in antiparallel dimerization of two peptide helices in the presence of Ca~(2+), but not Mg~(2+). A con-T variant, con-T[K7γ], displays very similar behavior. We have solved the crystal structures of both Ca~(2+)/con-G and Ca~(2+)/con-T [K7γ] at atomic resolution. These structures clearly show the nature of the metal-dependent dimerization and helix formation and surprisingly also show that the con-G dimer interface is completely different from the con-T[K7γ] interface, even though the metal chelation is similar in the two peptides. This represents a new paradigm in helix stabilization completely independent of the hydrophobic effect, which we define as the "metallo-zipper."