2JUS

alpha RgIA, a Novel Conotoxin that Blocks the alpha9-alpha10 nAChR

Summary for 2JUS

• Entry DOI: 10.2210/pdb2jus/pdb
• Related: 2JUQ 2JUR 2JUT
• Descriptor: Alpha-conotoxin RgIA (1 entity in total)
• Functional Keywords: two-loop backbone architecture, disulfide bond, signaling protein inhibitor, toxin
• Cellular location: Secreted (By similarity): P0C1D0
• Total number of polymer chains: 1
• Total formula weight: 1601.90

Authors

Feng, Z.,Ellison, M. (deposition date: 2007-09-02, release date: 2011-05-25, Last modification date: 2021-10-20)

Primary citation

Ellison, M.,Feng, Z.P.,Park, A.J.,Zhang, X.,Olivera, B.M.,McIntosh, J.M.,Norton, R.S.
Alpha-RgIA, a novel conotoxin that blocks the alpha9alpha10 nAChR: structure and identification of key receptor-binding residues.
J.Mol.Biol., 377:1216-1227, 2008

PubMed Abstract: Alpha-conotoxins are small disulfide-constrained peptides from cone snails that act as antagonists at specific subtypes of nicotinic acetylcholine receptors (nAChRs). The 13-residue peptide alpha-conotoxin RgIA (alpha-RgIA) is a member of the alpha-4,3 family of alpha-conotoxins and selectively blocks the alpha9alpha10 nAChR subtype, in contrast to another well-characterized member of this family, alpha-conotoxin ImI (alpha-ImI), which is a potent inhibitor of the alpha7 and alpha3beta2 nAChR subtypes. In this study, we have altered side chains in both the four-residue and the three-residue loops of alpha-RgIA, and have modified its C-terminus. The effects of these changes on activity against alpha9alpha10 and alpha7 nAChRs were measured; the solution structures of alpha-RgIA and its Y10W, D5E, and P6V analogues were determined from NMR data; and resonance assignments were made for alpha-RgIA [R9A]. The structures for alpha-RgIA and its three analogues were well defined, except at the chain termini. Comparison of these structures with reported structures of alpha-ImI reveals a common two-loop backbone architecture within the alpha-4,3 family, but with variations in side-chain solvent accessibility and orientation. Asp5, Pro6, and Arg7 in loop 1 are critical for blockade of both the alpha9alpha10 and the alpha7 subtypes. In loop 2, alpha-RgIA [Y10W] had activity near that of wild-type alpha-RgIA, with high potency for alpha9alpha10 and low potency for alpha7, and had a structure similar to that of wild type. By contrast, Arg9 in loop 2 is critical for specific binding to the alpha9alpha10 subtype, probably because it is larger and more solvent accessible than Ala9 in alpha-ImI. Our findings contribute to a better understanding of the molecular basis for antagonism of the alpha9alpha10 nAChR subtype, which is a target for the development of analgesics for the treatment of chronic neuropathic pain.

PubMed: 18295795
DOI: 10.1016/j.jmb.2008.01.082

Experimental method

SOLUTION NMR