Journal
BIOPHYSICAL JOURNAL
Volume 103, Issue 11, Pages 2331-2340Publisher
CELL PRESS
DOI: 10.1016/j.bpj.2012.10.034
Keywords
-
Categories
Funding
- U.S. Public Health Service [GM 069726, AA018316]
- Foundation for Anesthesia Education and Research award
- Department of Anesthesia, Critical Care & Pain Medicine, Massachusetts General Hospital
- State of California for medical research on alcohol and substance abuse through University of California, San Francisco
- National Center for Research Resources at the National Institutes of Health [RR-15301]
- National Institute of General Medical Sciences, National Institutes of Health [GM-0080]
- U.S. Department of Energy [DE-AC02-98CH10886]
Ask authors/readers for more resources
Elucidating the principles governing anesthetic-protein interactions requires structural determinations at high resolutions not yet achieved with ion channels. Protein kinase C (PKC) activity is modulated by general anesthetics. We solved the structure of the phorbol-binding domain (C1B) of PKC delta complexed with an ether (methoxymethylcycloprane) and with an alcohol (cyclopropylmethanol) at 1.36-angstrom resolution. The cyclopropane rings of both agents displace a single water molecule in a surface pocket adjacent to the phorbol-binding site, making van der Waals contacts with the backbone and/or side chains of residues Asn-237 to Ser-240. Surprisingly, two water molecules anchored in a hydrogen-bonded chain between Thr-242 and Lys-260 impart elasticity to one side of the binding pocket. The cyclopropane ring takes part in pi-acceptor hydrogen bonds with the amide of Met-239. There is a crucial hydrogen bond between the oxygen atoms of the anesthetics and the hydroxyl of Tyr-236. A Tyr-236-Phe mutation results in loss of binding. Thus, both van der Waals interactions and hydrogen-bonding are essential for binding to occur. Ethanol failed to bind because it is too short to benefit from both interactions. Cyclopropylmethanol inhibited phorbol-ester-induced PKC delta activity, but failed to do so in PKC delta containing the Tyr-236-Phe mutation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available