3UGL: Structural and functional characterization of an anesthetic binding site in the second cysteine-rich domain of protein kinase C delta

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 PKCdelta complexed with an ether (methoxymethylcycloprane) and with an alcohol (cyclopropylmethanol) at 1.36-A 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 PKCdelta activity, but failed to do so in PKCdelta containing the Tyr-236-Phe mutation.
PDB ID: 3UGLDownload
MMDB ID: 105697
PDB Deposition Date: 2011/11/2
Updated in MMDB: 2012/12
Experimental Method:
x-ray diffraction
Resolution: 1.357  Å
Source Organism:
Similar Structures:
Biological Unit for 3UGL: dimeric; determined by author
Molecular Components in 3UGL
Label Count Molecule
Proteins (2 molecules)
Proteine Kinase C Delta Type(Gene symbol: Prkcd)
Molecule annotation
Chemicals (9 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB