2AJW

Structure of the cyclic conotoxin MII-6

Summary for 2AJW

• Entry DOI: 10.2210/pdb2ajw/pdb
• Related: 2AK0
• NMR Information: BMRB: 6818
• Descriptor: Alpha-conotoxin MII (1 entity in total)
• Functional Keywords: alpha-helix, cyclic backbone, toxin
• Cellular location: Secreted: P56636
• Total number of polymer chains: 1
• Total formula weight: 2088.33

Authors

Clark, R.J.,Fischer, H.,Dempster, L.,Daly, N.L.,Rosengren, K.J.,Nevin, S.T.,Meunier, F.A.,Adams, D.J.,Craik, D.J. (deposition date: 2005-08-02, release date: 2005-09-06, Last modification date: 2024-11-13)

Primary citation

Clark, R.J.,Fischer, H.,Dempster, L.,Daly, N.L.,Rosengren, K.J.,Nevin, S.T.,Meunier, F.A.,Adams, D.J.,Craik, D.J.
Engineering stable peptide toxins by means of backbone cyclization: Stabilization of the {alpha}-conotoxin MII.
Proc.Natl.Acad.Sci.USA, 102:13767-13772, 2005

PubMed Abstract: Conotoxins (CTXs), with their exquisite specificity and potency, have recently created much excitement as drug leads. However, like most peptides, their beneficial activities may potentially be undermined by susceptibility to proteolysis in vivo. By cyclizing the alpha-CTX MII by using a range of linkers, we have engineered peptides that preserve their full activity but have greatly improved resistance to proteolytic degradation. The cyclic MII analogue containing a seven-residue linker joining the N and C termini was as active and selective as the native peptide for native and recombinant neuronal nicotinic acetylcholine receptor subtypes present in bovine chromaffin cells and expressed in Xenopus oocytes, respectively. Furthermore, its resistance to proteolysis against a specific protease and in human plasma was significantly improved. More generally, to our knowledge, this report is the first on the cyclization of disulfide-rich toxins. Cyclization strategies represent an approach for stabilizing bioactive peptides while keeping their full potencies and should boost applications of peptide-based drugs in human medicine.

PubMed: 16162671
DOI: 10.1073/pnas.0504613102

Experimental method

SOLUTION NMR