7tvr

From Proteopedia

Structure of the ribbon isoform of the novel conotoxin PnID derived from Conus pennaceus

Structural highlights

7tvr is a 1 chain structure with sequence from Conus pennaceus. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR, 20 models
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CTA1_CONPE Chi-conotoxins inhibit the neuronal noradrenaline transporter (NET/SLC6A2). Of the 3 native isomers, only the isomer with a ribbon disulfide configuration shows pharmacological activity and 3D structure similar to other chi-conotoxins. This ribbon isomer (disulfide pattern: C1-C4 and C2-C3) inhibits the rat norepinephrine transporter (IC(50)=10 uM). In contrast, the globular isomer of PnID shows more than ten times less activity against this transporter and the beaded isomer does not display any measurable biological activity.^[1]

Publication Abstract from PubMed

chi-Conotoxins are known for their ability to selectively inhibit norepinephrine transporters, an ability that makes them potential leads for treating various neurological disorders, including neuropathic pain. PnID, a peptide isolated from the venom of Conus pennaceus, shares high sequence homology with previously characterized chi-conotoxins. Whereas previously reported chi-conotoxins seem to only have a single native disulfide bonding pattern, PnID has three native isomers due to the formation of different disulfide bond patterns during its maturation in the venom duct. In this study, the disulfide connectivity and three-dimensional structure of these disulfide isomers were explored using regioselective synthesis, chromatographic coelution, and solution-state nuclear magnetic resonance spectroscopy. Of the native isomers, only the isomer with a ribbon disulfide configuration showed pharmacological activity similar to other chi-conotoxins. This isomer inhibited the rat norepinephrine transporter (IC(50) = 10 +/- 2 microM) and has the most structural similarity to previously characterized chi-conotoxins. In contrast, the globular isoform of PnID showed more than ten times less activity against this transporter and the beaded isoform did not display any measurable biological activity. This study is the first report of the pharmacological and structural characterization of an chi-conotoxin from a species other than Conus marmoreus and is the first report of the existence of natively-formed conotoxin isomers.

Characterization of the Native Disulfide Isomers of the Novel chi-Conotoxin PnID: Implications for Further Increasing Conotoxin Diversity.,Espiritu MJ, Taylor JK, Sugai CK, Thapa P, Loening NM, Gusman E, Baoanan ZG, Baumann MH, Bingham JP Mar Drugs. 2023 Jan 19;21(2):61. doi: 10.3390/md21020061. PMID:36827103^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Espiritu MJ, Taylor JK, Sugai CK, Thapa P, Loening NM, Gusman E, Baoanan ZG, Baumann MH, Bingham JP. Characterization of the Native Disulfide Isomers of the Novel χ-Conotoxin PnID: Implications for Further Increasing Conotoxin Diversity. Mar Drugs. 2023 Jan 19;21(2):61. PMID:36827103 doi:10.3390/md21020061
↑ Espiritu MJ, Taylor JK, Sugai CK, Thapa P, Loening NM, Gusman E, Baoanan ZG, Baumann MH, Bingham JP. Characterization of the Native Disulfide Isomers of the Novel χ-Conotoxin PnID: Implications for Further Increasing Conotoxin Diversity. Mar Drugs. 2023 Jan 19;21(2):61. PMID:36827103 doi:10.3390/md21020061