6KMY
Structure of single disulfide peptide Czon1107-P5A
Summary for 6KMY
| Entry DOI | 10.2210/pdb6kmy/pdb |
| Descriptor | Czon1107-P5A (1 entity in total) |
| Functional Keywords | nachr anatgonist nmr, neuropeptide |
| Biological source | Conus zonatus |
| Total number of polymer chains | 1 |
| Total formula weight | 1083.29 |
| Authors | Sarma, S.P.,Madhan Kumar, M. (deposition date: 2019-08-01, release date: 2020-04-08, Last modification date: 2024-10-23) |
| Primary citation | Mohan, M.K.,Abraham, N.,R P, R.,Jayaseelan, B.F.,Ragnarsson, L.,Lewis, R.J.,Sarma, S.P. Structure and allosteric activity of a single-disulfide conopeptide fromConus zonatusat human alpha 3 beta 4 and alpha 7 nicotinic acetylcholine receptors. J.Biol.Chem., 295:7096-7112, 2020 Cited by PubMed Abstract: Conopeptides are neurotoxic peptides in the venom of marine cone snails and have broad therapeutic potential for managing pain and other conditions. Here, we identified the single-disulfide peptides Czon1107 and Cca1669 from the venoms of and , respectively. We observed that Czon1107 strongly inhibits the human α3β4 (IC 15.7 ± 3.0 μm) and α7 (IC 77.1 ± 0.05 μm) nicotinic acetylcholine receptor (nAChR) subtypes, but the activity of Cca1669 remains to be identified. Czon1107 acted at a site distinct from the orthosteric receptor site. Solution NMR experiments revealed that Czon1107 exists in equilibrium between conformational states that are the result of a key Ser-Pro isomerization. Moreover, we found that the X-Pro amide bonds in the inter-cysteine loop are rigidly constrained to conformations. Structure-activity experiments of Czon1107 and its variants at positions P5 and P7 revealed that the conformation around the X-Pro bonds () plays an important role in receptor subtype selectivity. The conformation at the Cys-Pro peptide bond was essential for α3β4 nAChR subtype allosteric selectivity. In summary, we have identified a unique single-disulfide conopeptide with a noncompetitive, potentially allosteric inhibitory mechanism at the nAChRs. The small size and rigidity of the Czon1107 peptide could provide a scaffold for rational drug design strategies for allosteric nAChR modulation. This new paradigm in the "conotoxinomic" structure-function space provides an impetus to screen venom from other species for similar, short bioactive peptides that allosterically modulate ligand-gated receptor function. PubMed: 32234761DOI: 10.1074/jbc.RA119.012098 PDB entries with the same primary citation |
| Experimental method | SOLUTION NMR |
Structure validation
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