Conformationally constrained analogues of diacylglycerol (DAG). 15. The indispensable role of the sn-1 and sn-2 carbonyls in the binding of DAG-lactones to protein kinase C (PK-C).
The binding mode of DAG-lactones to PK-C was investigated using the C1b domain from the X-ray structure of the phorbol ester/C1b complex of PK-C delta as a template. Modeling experiments revealed two binding alternatives in which one of the carbonyls of the DAG lactones remained uninvolved with the protein. Experimentally, however, the removal of either sn-1 or sn-2 carbonyls caused a dramatic drop in binding affinity towards PK-C. Although it was not possible to discriminate between the two binding alternatives of the DAG-lactones, the study demonstrates an important role for the additional carbonyl group. The function of this group could be equivalent to that of the C-9(OH)/C-13 (C = O) motif in phorbol esters, which also appears free of interactions in the phorbol ester/C1b complex. This role presumably reflects interaction with the phosholipid head groups required for high affinity binding under the conditions of the biological assays.
Benzaria
S
S
Laboratory of Medicinal Chemistry, National Institutes of Health, Bethesda, MD 20892, USA.
Bienfait
B
B
Nacro
K
K
Wang
S
S
Lewin
N E
NE
Beheshti
M
M
Blumberg
P M
PM
Marquez
V E
VE
D004075:Diglycerides / Q000138:chemical synthesis / Q000378:metabolism*; D006860:Hydrogen Bonding; D007783:Lactones / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D011493:Protein Kinase C / Q000378:metabolism*; D013329:Structure-Activity Relationship
D004075:Diglycerides; D007783:Lactones; D011493:Protein Kinase C