Conformation of sarafotoxin‐6b in aqueous solution determined by NMR spectroscopy and distance geometry

Abstract

The solution ~tructure of sarafoloxln .(~b in water has been determined ufing high.resolution NM R spcctr0s¢opy, 12"/proton=prolon diflance mea~. urements and three ~ dihedral an~le conltraint~ derived from NMR spectra were used to calculate the solution structure t,~lnll =t con~hination of distance geometry and restrained molecular dynamic=¢. The major structural feature of the resulting family of five structures was a right.her, tied =.helix extending from K9 to QI?. In contrast, the C.terminal region of the pcptkle appears not to adopt a preferred conformation in aqueous solution, The present atructure i =~ compared with those previottslydetcrmined for endothelin peptides In non.aqueou~ solvents,

Engineered Sarafotoxins as Tissue Inhibitor of Metalloproteinases-like Matrix Metalloproteinase Inhibitors

“…5). This result is similar to the crystal struc- tures of ET family members in which the C terminus is largely helical (6,8,45).…”

“…A member of the ET family whose solution structure has been determined (6,45), sarafotoxin 6b (Srt6b) (Fig. 1), was initially tested for MMP inhibitory activity and was found to inhibit MMP-2 and MMP-3 with K i values of 4 and 8 M, respectively (data not shown).…”

“…NMR and crystallographic studies reveal that these peptides contain a bicyclic two-disulfide (Cys 1 -Cys 15 , Cys 3 -Cys 11 ) framework with a specific tertiary structure. The N-terminal residues form a ␤-strand followed by a ␤-turn at residue 5 (5); residues 9 -16 are mainly ␣-helical, whereas the C-terminal residues are flexible in solution (6). However, the crystal structure and protease susceptibility studies suggest that these C-terminal residues may associate with the bicyclic core as an ␣-helix (7,8).…”

Solution conformation of a cyclic pentapeptide endothelin antagonist Comparison of structures obtained from constrained dynamics and conformational search

“…There appears to be some analogy to the endothelin C-terminus. In the case of endothelins (and samfotoxin 6b), one of the methyl groups in residue 19 appears at unusually low chemical shift and large NOE connectivities between residues 19 and 21 are observed [8,27,28]. The structuring of the C-terminus of endothelins in aqueous media may be governed by a similar hydrophobic interaction.…”

Synthesis of single‐ and multiple‐stranded cystine‐rich peptides

“…Taking into account the possible connectivities of the consensus cysteine pattern Cys(Xaa) 1 Cys/Cys(Xaa) 3 Cys in short natural peptides, the peptide backbones can be arranged in parallel or antiparallel manner,8, 24, 30 as observed for the bee venom toxins apamin31 or mast cell degranulating peptide (MCD),32 and for human endothelins24, 33–38 or the related reptilian sarafotoxin 6b,39–41 respectively. The parallel alignment leads to a more compact globular structure than the antiparallel alignment; correspondingly, these isomers were symbolically named the globule and ribbon isomer (Figure 2).…”