6klm

NMR solution structure of Roseltide rT7NMR solution structure of Roseltide rT7

Structural highlights 6klm is a 1 chain structure with sequence from Hibiscus sabdariffa. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Solution NMR, 17 models Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Disulfide-rich plant peptides with molecular weights of 2 to 6 kDa represent an expanding class of peptidyl-type natural products with diverse functions. They are structurally compact, hyperstable, and underexplored as cell-penetrating agents that inhibit intracellular functions. Here, we report the discovery of an anionic, 34-residue-peptide, the disulfide-rich roseltide rT7 from Hibiscus sabdariffa (of the Malvaceae family), that penetrates cells and inhibits their proteasomal activities. Combined proteomics and NMR spectroscopy revealed that roseltide rT7 is a cystine-knotted, 6C-hevein-like cysteine-rich peptide. A pair-wise comparison indicated that roseltide rT7 is > 100-fold more stable against protease degradation than its S-alkylated analog. Confocal microscopy studies and cell-based assays disclosed that after roseltide rT7 penetrates cells, it causes accumulation of ubiquitinated proteins, inhibits human 20S proteasomes, reduces tumor necrosis factor-induced IkappaBC; degradation, and decreases expression levels of intercellular adhesion molecule-1. Structure-activity studies revealed that roseltide rT7 uses a canonical substrate-binding mechanism for proteasomal inhibition enabled by an IIML motif embedded in its proline-rich and exceptionally long intercysteine loop 4. Taken together, our results provide mechanistic insights into a novel disulfide-rich, anionic, and cell-penetrating peptide, representing a potential lead for further development as a proteasomal inhibitor in anti-cancer or anti-inflammatory therapies. Roseltide rT7 is a disulfide-rich, anionic, and cell-penetrating peptide that inhibits proteasomal degradation.,Kam A, Loo S, Fan JS, Sze SK, Yang D, Tam JP J Biol Chem. 2019 Nov 14. pii: RA119.010796. doi: 10.1074/jbc.RA119.010796. PMID:31727740 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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