期刊
NATURE CHEMICAL BIOLOGY
卷 9, 期 11, 页码 715-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1340
关键词
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资金
- Medical Research Council (UK) [G0901892]
- US National Institutes of Health (NIH) - National Institute of General Medical Sciences [PO1-GM47969, 8 P41 GM103422-35]
- Austrian Ministry of Science and Research
- European Seventh Framework Program [HEALTH-F4-2008-202088]
- MRC [G0901892] Funding Source: UKRI
- Medical Research Council [G0901892] Funding Source: researchfish
Propofol is the most important intravenous general anesthetic in current clinical use. It acts by potentiating GABA(A) (gamma-aminobutyric acid type A) receptors, but where it binds to this receptor is not known and has been a matter of some debate. We synthesized a new propofol analog photolabeling reagent whose biological activity is very similar to that of propofol. We confirmed that this reagent labeled known propofol binding sites in human serum albumin that have been identified using X-ray crystallography. Using a combination of protiated and deuterated versions of the reagent to label mammalian receptors in intact membranes, we identified a new binding site for propofol in GABA(A) receptors consisting of both beta(3) homopentamers and alpha(1)beta(3) heteropentamers. The binding site is located within the beta subunit at the interface between the transmembrane domains and the extracellular domain and lies close to known determinants of anesthetic sensitivity in the transmembrane segments TM1 and TM2.
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