Benzaria S, Bienfait B, Nacro K, Wang S, Lewin N E, Beheshti M, Blumberg P M, Marquez V E
Laboratory of Medicinal Chemistry, National Institutes of Health, Bethesda, MD 20892, USA.
Bioorg Med Chem Lett. 1998 Dec 1;8(23):3403-8. doi: 10.1016/s0960-894x(98)00614-3.
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.
以蛋白激酶Cδ的佛波酯/C1b复合物的X射线结构中的C1b结构域为模板，研究了二酰甘油内酯与蛋白激酶C的结合模式。建模实验揭示了两种结合方式，其中二酰甘油内酯的一个羰基未与蛋白质发生相互作用。然而，实验表明，去除sn-1或sn-2羰基会导致对蛋白激酶C的结合亲和力急剧下降。虽然无法区分二酰甘油内酯的两种结合方式，但该研究证明了额外羰基基团的重要作用。该基团的功能可能等同于佛波酯中C-9(OH)/C-13 (C = O)基序的功能，在佛波酯/C1b复合物中该基序似乎也没有相互作用。这种作用可能反映了在生物测定条件下与高亲和力结合所需的磷脂头部基团的相互作用。
