title: Racemic and quasi-racemic X-ray structures of cyclic disulfide-rich peptide drug scaffolds.
abstract: Cyclic disulfide-rich peptides have exceptional stability and are promising frameworks for drug design. We were interested in obtaining X-ray structures of these peptides to assist in drug design applications, but disulfide-rich peptides can be notoriously difficult to crystallize. To overcome this limitation, we chemically synthesized the L- and D-forms of three 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) for racemic crystallization studies. Facile crystal formation occurred from a racemic mixture of each peptide, giving structures solved at resolutions from 1.25 Å to 1.9 Å. Additionally, we obtained the quasi-racemic structures of two mutants of kB1, [G6A]kB1, and [V25A]kB1, which were solved at a resolution of 1.25 Å and 2.3 Å, respectively. The racemic crystallography approach appears to have broad utility in the structural biology of cyclic peptides.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Qld, 4072 (Australia).
authors.forename: Conan K
authors.initials: CK
authors.lastname: Wang
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: King
authors.forename: Susan E
authors.initials: SE
authors.lastname: Northfield
authors.forename: Paola G
authors.initials: PG
authors.lastname: Ojeda
authors.forename: David J
authors.initials: DJ
authors.lastname: Craik
mesh_terms: D000595:Amino Acid Sequence; D003460:Crystallization; D018360:Crystallography, X-Ray; D004220:Disulfides / Q000737:chemistry*; D015195:Drug Design; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D004220:Disulfides; D010456:Peptides, Cyclic
keywords: D-amino acids; crystal structures; cyclic peptides; disulfide bonds; racemic crystallography