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 dom ain from the Xray structure of the phorbol ester/C1b complex of PK-C delta as a template. Modeling experiments revealed two binding alternatives in wh ich one of the carbonyls of the DAG lactones remained uninvolved with the p rotein. Experimentally, however, the removal of either sn-1 or sn-2 carbony ls caused a dramatic drop in binding affinity towards PK-C. Although it was not possible to discriminate between the two binding alternatives of the D AG-lactones, the study demonstrates an important role for the additional ca rbonyl group. The function of this group could be equivalent to that of the C-9(OH)/C-13 (C=O) motif in phorbol eaters, which also appears free of int eractions in the phorbol ester/C1b complex. This role presumably reflects i nteraction with the phosholipid head groups required for high affinity bind ing under the conditions of the biological assays. (C) 1998 Elsevier Scienc e Ltd. All rights reserved.