Evidence for an Extended Hydrogen Bond Network in the Binding Site of the Nicotinic Receptor

The defining feature of the α subunits of the family of nicotinic acetylcholine receptors is a vicinal disulfide between Cys-192 and Cys-193. Although this structure has played a pivotal role in a number of pioneering studies of nicotinic receptors, its functional role in native receptors remains un...

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Bibliographic Details
Published in:The Journal of biological chemistry 2011-09, Vol.286 (37), p.32251-32258
Main Authors: Blum, Angela P., Gleitsman, Kristin Rule, Lester, Henry A., Dougherty, Dennis A.
Format: Article
Language:English
Subjects:
Ion channels
Mutant
Nicotinic Acetylcholine Receptors
Protein Chemistry
Protein-Drug Interactions
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Summary:The defining feature of the α subunits of the family of nicotinic acetylcholine receptors is a vicinal disulfide between Cys-192 and Cys-193. Although this structure has played a pivotal role in a number of pioneering studies of nicotinic receptors, its functional role in native receptors remains uncertain. Using mutant cycle analysis and unnatural residue mutagenesis, including backbone mutagenesis of the peptide bond of the vicinal disulfide, we have established the presence of a network of hydrogen bonds that extends from that peptide NH, across a β turn to another backbone hydrogen bond, and then across the subunit interface to the side chain of a functionally important Asp residue in the non-α subunit. We propose that the role of the vicinal disulfide is to distort the β turn and thereby properly position a backbone NH for intersubunit hydrogen bonding to the key Asp.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M111.254235