1JLP

Solution Structure of the Noncompetitive Skeletal Muscle Nicotinic Acetylcholine Receptor Antagonist Psi-conotoxin PIIIF

Summary for 1JLP

• Entry DOI: 10.2210/pdb1jlp/pdb
• Related: 1AS5 1JLO
• NMR Information: BMRB: 5112
• Descriptor: PSI-CONOTOXIN PIIIF (1 entity in total)
• Functional Keywords: multiple disulfide bonds, amidated c-terminus, toxin
• Cellular location: Secreted: P60245
• Total number of polymer chains: 1
• Total formula weight: 2674.16

Authors

Van Wagoner, R.M.,Ireland, C.M. (deposition date: 2001-07-16, release date: 2003-06-24, Last modification date: 2022-02-23)

Primary citation

Van Wagoner, R.M.,Ireland, C.M.
Characterization and Three-Dimensional Structure Determination of psi-Conotoxin Piiif, a Novel Noncompetitive Antagonist of Nicotinic Acetylcholine Receptors
Biochemistry, 42:6353-6362, 2003

PubMed Abstract: A novel inhibitor of nicotinic acetylcholine receptors (nAChRs), psi-conotoxin Piiif, was isolated from the venom of Conus purpurascens and found to have the sequence GOOCCLYGSCROFOGCYNALCCRK-NH2. The sequence is highly homologous to that of psi-conotoxin Piiie, a previously identified noncompetitive inhibitor of Torpedo electroplax nAChR, also isolated from C. purpurascens. Both psi-conotoxins block Torpedo and mouse nicotinic acetylcholine receptors (nAChRs), but psi-Piiif is less potent by a factor of 10(1)-10(2). A high-resolution structure of psi-Piiif was determined by NMR and molecular modeling calculations. Psi-Piiif analogues containing [(13)C]-labeled cysteine at selected positions were synthesized to resolve spectral overlap of Cys side chain proton signals. The structures are well-converged, with backbone atom position RMSDs of 0.21 A for the main body of the peptide between residues 4 and 22 and 0.47 A for all residues. The overall backbone conformation is closely similar to psi-Piiie, the main difference being in the degree of conformational disorder at the two termini. Psi-Piiie and psi-Piiif have similar locations of positive charge density, although psi-Piiif has a lower overall charge. One disulfide bridge of psi-Piiif appears to undergo dynamic conformational fluctuations based on both the model and on experimental observation. Chimeras in which the three intercysteine loops were swapped between psi-Piiie and psi-Piiif were tested for inhibitory activity against Torpedo nAChRs. The third loop, which contains no charged residues in either peptide, is the prime determinant of potency in these psi-conotoxins.

PubMed: 12767216
DOI: 10.1021/bi0272757

Experimental method

SOLUTION NMR