A helping hand for peptide structure and function

CK Wang and DJ Craik

The University of Queensland

Peptides (mini-proteins) are ubiquitous in Nature, serve a myriad of functions vital for life and are promising modalities for drug design. For example, cyclic disulfide-rich peptides have great therapeutic potential in many diseases including multiple sclerosis (Wang et al 2013 ACS Chem Biol), amyloid-related diseases (Wang et al 2016 Eur J Med Chem) and cancer (Huang et al 2015 Sci Rep). To further our understanding of function and potential applications of peptides, many studies have looked to an understanding of structure for inspiration. Given the importance of structure, we sought to address the long-standing challenge of obtaining high-resolution crystal structures of peptides, which has been notoriously difficult because of the 'crystallisation bottleneck'. Excitingly, recent advances in racemic crystallography, in which crystals are grown from a mixture containing a peptide and its mirror image, promise a way to obtain facile crystal growth. In this talk, I will discuss how we have used this approach to elucidate high-resolution crystal structures of a range of prototypic cyclic disulfide-rich peptides: SFTI-1 (14-mer with one disulfide bond), cVc1.1 (22-mer with two disulfide bonds), and kB1 (29-mer with three disulfide bonds), as well as their analogues (Wang et al 2015 Angew Chem Int). Additionally, we crystallised a cyclic 18-mer antimicrobial peptide from baboons, called BTD-2 (Wang et al 2016 J Am Chem Soc). The structure solved at 1.45 Å revealed a novel supramolecular assembly that might represent the active form of BTD-2 and also resembles a fibril-like assembly, providing an intriguing and perhaps provocative structural link to amyloid-forming proteins. I hope that this talk will inspire others to examine more closely both right- and left-handed forms of peptides, as in some cases two hands are better than one.