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Protein-engineering methods have been exploited to produce a surrogate system for the extracellular neurotransmitter-binding site of a heteromeric human ligand-gated ion channel, the glycine receptor. This approach circumvents two major issues: the inherent experimental difficulties in working with a membrane-bound ion channel and the complication that a heteromeric assembly is necessary to create a key, physiologically relevant binding site. Residues that form the orthosteric site in a highly stable ortholog, acetylcholine-binding protein, were selected for substitution. Recombinant proteins were prepared and characterized in stepwise fashion exploiting a range of biophysical techniques, including X-ray crystallography, married to the use of selected chemical probes. The decision making and development of the surrogate, which is termed a glycine-binding protein, are described, and comparisons are provided with wild-type and homomeric systems that establish features of molecular recognition in the binding site and the confidence that the system is suited for use in early-stage drug discovery targeting a heteromeric α/β glycine receptor.
|Number of pages||10|
|Issue number||Part 6|
|Early online date||4 Sept 2019|
|Publication status||Published - 1 Nov 2019|
- Acetylcholine-binding protein
- crystal structures
- glycine receptor
- ligand-gated ion channel
- acetylcholine-binding protein
ASJC Scopus subject areas
- Condensed Matter Physics
- Materials Science(all)
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- 1 Finished
State-of-the-Art Facilities for Structural Biology at the University of Dundee
Hunter, B., Lilley, D., Owen-Hughes, T., Wyatt, P. & van Aalten, D.
1/03/12 → 28/02/17