Journal
STRUCTURE
Volume 20, Issue 9, Pages 1463-1469Publisher
CELL PRESS
DOI: 10.1016/j.str.2012.08.009
Keywords
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Funding
- DOE Office of Biological and Environmental Research
- National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]
- National Center for Research Resources [P41RR001209]
- NIH [R01GM066358, R01GM056257, R37GM049202, T32GM075770]
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Pentameric ligand-gated ion channels (pLGICs) are targets of general anesthetics, but a structural understanding of anesthetic action on pLGICs remains elusive. GLIC, a prokaryotic pLGIC, can be inhibited by anesthetics, including ketamine. The ketamine concentration leading to half-maximal inhibition of GLIC (58 mu M) is comparable to that on neuronal nicotinic acetylcholine receptors. A 2.99 angstrom resolution X-ray structure of GLIC bound with ketamine revealed ketamine binding to an intersubunit cavity that partially overlaps with the homologous antagonist-binding site in pLGICs. The functional relevance of the identified ketamine site was highlighted by profound changes in GLIC activation upon cysteine substitution of the cavity-lining residue N152. The relevance is also evidenced by changes in ketamine inhibition upon the subsequent chemical labeling of N152C. The results provide structural insight into the molecular recognition of ketamine and are valuable for understanding the actions of anesthetics and other allosteric modulators on pLGICs.
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