7TXF

The allosteric binding mode of alphaD-conotoxin VxXXB

Summary for 7TXF

• Entry DOI: 10.2210/pdb7txf/pdb
• Descriptor: Acetylcholine-binding protein, Alpha-conotoxin VxXXB (2 entities in total)
• Functional Keywords: alpha-conotoxin, complex, acetylcholine-binding protein, choline-binding protein-antagonist complex, peptide binding protein
• Biological source: Lymnaea stagnalis; More
• Total number of polymer chains: 8
• Total formula weight: 126243.73

Authors

Ho, T.N.T.,Abraham, N.,Lewis, R.J. (deposition date: 2022-02-09, release date: 2023-04-12, Last modification date: 2024-10-16)

Primary citation

Ho, T.N.,Abraham, N.,Lewis, R.J.
Unravelling the allosteric binding mode of alpha D-VxXXB at nicotinic acetylcholine receptors.
Front Pharmacol, 14:1170514-1170514, 2023

PubMed Abstract: αD-conotoxins are 11 kDa homodimers that potently inhibit nicotinic acetylcholine receptors (nAChRs) through a non-competitive (allosteric) mechanism. In this study, we describe the allosteric binding mode of the granulin-like C-terminal (CTD) of VxXXB bound to acetylcholine binding protein (-AChBP), a soluble homologue of the extracellular ligand-binding domain of nAChRs. This co-crystal complex revealed a novel allosteric binding site for nAChR antagonists outside the C-loop that caps the orthosteric site defined by the nAChR agonist nicotine and the antagonist epibatidine. Mutational and docking studies on -AChBP supported a two-site binding mode for full-length VxXXB, with the first CTD binding site located outside the C-loop as seen in the co-crystal complex, with a second CTD binding site located near the N-terminal end of the adjacent subunit of AChBP. These results provide new structural insight into a novel allosteric mechanism of nAChR inhibition and define the cooperative binding mode of the N-terminal domain linked granulin core domains of αD-conotoxins.

PubMed: 37124228
DOI: 10.3389/fphar.2023.1170514

Experimental method

X-RAY DIFFRACTION (2.47 Å)