期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：43
页码：13144-13149
DOI：10.1073/pnas.1507918112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceD polypeptides represent an attractive platform for biomedical applications because of their resistance to proteolytic degradation. However, the structural principles that underlie associations between L- and D-protein partners remain poorly understood because there has been very little atomic-resolution structural characterization of such heterochiral assemblies. Here we report two X-ray crystal structures of the racemic form of an -helical peptide derived from the influenza M2 protein. Both structures contain large heterochiral coiled-coil interfaces. The ubiquity and regularity of coiled coils has inspired extensive design effort directed toward homochiral tertiary and quaternary structures, and we anticipate that the insights from these crystal structures will facilitate the design of an analogous rich set of heterochiral proteins and assemblies. Interactions between polypeptide chains containing amino acid residues with opposite absolute configurations have long been a source of interest and speculation, but there is very little structural information for such heterochiral associations. The need to address this lacuna has grown in recent years because of increasing interest in the use of peptides generated from D amino acids (D peptides) as specific ligands for natural proteins, e.g., to inhibit deleterious protein-protein interactions. Coiled-coil interactions, between or among -helices, represent the most common tertiary and quaternary packing motif in proteins. Heterochiral coiled-coil interactions were predicted over 50 years ago by Crick, and limited experimental data obtained in solution suggest that such interactions can indeed occur. To address the dearth of atomic-level structural characterization of heterochiral helix pairings, we report two independent crystal structures that elucidate coiled-coil packing between L- and D-peptide helices. Both structures resulted from racemic crystallization of a peptide corresponding to the transmembrane segment of the influenza M2 protein. Networks of canonical knobs-into-holes side-chain packing interactions are observed at each helical interface. However, the underlying patterns for these heterochiral coiled coils seem to deviate from the heptad sequence repeat that is characteristic of most homochiral analogs, with an apparent preference for a hendecad repeat pattern.
