Source:http://linkedlifedata.com/resource/pubmed/id/11384235
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
12
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| pubmed:dateCreated |
2001-5-31
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| pubmed:abstractText |
A small, focused combinatorial library encompassing all possible permutations of acyl branched alkyl chains-small and large, saturated and unsaturated-was generated from the active diacylglycerol enantiomer (S-DAG) to help identify the analogue with the highest binding affinity (lowest Ki) for protein kinase C (PK-C) combined with the minimum lipophilicity (log P). The selected ligand (3B) activated PK-C more effectively than sn-1,2-dioctanoylglycerol (diC8) despite being 1.4 log units more hydrophilic. Compound 3B indeed represents the most potent, hydrophilic DAG ligand to date. With the help of a green fluorescent protein (GFP)-tagged PK-Calpha, 3B was able to translocate the full length protein to the membrane with an optimal dose of 100 microM in CHO-K1 cells, while diC8 failed to achieve translocation even at doses 3-fold higher. Molecular modeling of 3B into an empty C1b domain of PK-Cdelta clearly showed the existence of a preferred binding orientation. In addition, molecular dynamic simulations suggest that binding discrimination could result from a favorable van der Waals (VDW) interaction between the large, branched sn-1 acyl group of 3B and the aromatic rings of Trp252 (PK-Cdelta) or Tyr252 (PK-Calpha). The DAG analogue of 3B in which the acyl groups are reversed (2C) showed a decrease in binding affinity reflecting the capacity of PK-C to effectively discriminate between alternative orientations of the acyl chains.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Diglycerides,
http://linkedlifedata.com/resource/pubmed/chemical/Phorbol 12,13-Dibutyrate,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase C,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Tryptophan,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrosine
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| pubmed:status |
MEDLINE
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| pubmed:month |
Jun
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| pubmed:issn |
0022-2623
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| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
7
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| pubmed:volume |
44
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
1892-904
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| pubmed:dateRevised |
2007-11-15
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| pubmed:meshHeading |
pubmed-meshheading:11384235-Animals,
pubmed-meshheading:11384235-Binding, Competitive,
pubmed-meshheading:11384235-Binding Sites,
pubmed-meshheading:11384235-CHO Cells,
pubmed-meshheading:11384235-Cricetinae,
pubmed-meshheading:11384235-Databases as Topic,
pubmed-meshheading:11384235-Diglycerides,
pubmed-meshheading:11384235-Enzyme Activation,
pubmed-meshheading:11384235-Hydrogen Bonding,
pubmed-meshheading:11384235-Kinetics,
pubmed-meshheading:11384235-Models, Molecular,
pubmed-meshheading:11384235-Molecular Conformation,
pubmed-meshheading:11384235-Phorbol 12,13-Dibutyrate,
pubmed-meshheading:11384235-Protein Conformation,
pubmed-meshheading:11384235-Protein Kinase C,
pubmed-meshheading:11384235-Protein Structure, Secondary,
pubmed-meshheading:11384235-Recombinant Fusion Proteins,
pubmed-meshheading:11384235-Structure-Activity Relationship,
pubmed-meshheading:11384235-Transfection,
pubmed-meshheading:11384235-Tryptophan,
pubmed-meshheading:11384235-Tyrosine,
pubmed-meshheading:11384235-Zinc Fingers
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| pubmed:year |
2001
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| pubmed:articleTitle |
An optimized protein kinase C activating diacylglycerol combining high binding affinity (Ki) with reduced lipophilicity (log P).
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| pubmed:affiliation |
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.
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| pubmed:publicationType |
Journal Article
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