Squash inhibitors: from structural motifs to macrocyclic knottins.
In this article, we will first introduce the squash inhibitor, a well established family of highly potent canonical serine proteinase inhibitors isolated from Cucurbitaceae. The squash inhibitors were among the first discovered proteins with the typical knottin fold shared by numerous peptides extracted from plants, animals and fungi. Knottins contain three knotted disulfide bridges, two of them arranged as a Cystine-Stabilized Beta-sheet motif. In contrast to cyclotides for which no natural linear homolog is known, most squash inhibitors are linear. However, Momordica cochinchinensis Trypsin Inhibitor-I and (MCoTI-I and -II), 34-residue squash inhibitors isolated from seeds of a common Cucurbitaceae from Vietnam, were recently shown to be macrocyclic. In these circular squash inhibitors, a short peptide linker connects residues that correspond to the N- and C-termini in homologous linear squash inhibitors. In this review we present the isolation, characterization, chemical synthesis, and activity of these macrocyclic knottins. The solution structure of MCoTI-II will be compared with topologically similar cyclotides, homologous linear squash inhibitors and other knottins, and potential applications of such scaffolds will be discussed.
Chiche
Laurent
L
Centre de Biochimie Structurale, CNRS UMR5048, INSERM UMR554, Université Montpellier I, Faculté de Pharmacie, 34093 Montpellier, France. chiche@cbs.cnrs.fr
Heitz
Annie
A
Gelly
Jean-Christophe
JC
Gracy
Jérôme
J
Chau
Pham T T
PT
Ha
Phan T
PT
Hernandez
Jean-François
JF
Le-Nguyen
Dung
D
D000595:Amino Acid Sequence; D028464:Cucurbita / Q000737:chemistry*; D003500:Cyclization; D015195:Drug Design; D006801:Humans; D008969:Molecular Sequence Data; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology
D011506:Proteins; D015842:Serine Proteinase Inhibitors