Source:http://linkedlifedata.com/resource/pubmed/id/15481978
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
22
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| pubmed:dateCreated |
2004-10-14
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| pubmed:abstractText |
The Src Homology 3 (SH3) domains are small protein-protein interaction domains that bind proline-rich sequences and mediate a wide range of cell-signaling and other important biological processes. Since deregulated signaling pathways form the basis of many human diseases, the SH3 domains have been attractive targets for novel therapeutics. High-affinity ligands for SH3 domains have been designed; however, these have all been peptide-based and no examples of entirely nonpeptide SH3 ligands have previously been reported. Using the mouse Tec Kinase SH3 domain as a model system for structure-based ligand design, we have identified several simple heterocyclic compounds that selectively bind to the Tec SH3 domain. Using a combination of nuclear magnetic resonance chemical shift perturbation, structure-activity relationships, and site-directed mutagenesis, the binding of these compounds at the proline-rich peptide-binding site has been characterized. The most potent of these, 2-aminoquinoline, bound with Kd = 125 microM and was able to compete for binding with a proline-rich peptide. Synthesis of 6-substituted-2-aminoquinolines resulted in ligands with up to 6-fold improved affinity over 2-aminoquinoline and enhanced specificity for the Tec SH3 domain. Therefore, 2-aminoquinolines may potentially be useful for the development of high affinity small molecule ligands for SH3 domains.
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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/Aminoquinolines,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/Proline,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Quinazolines,
http://linkedlifedata.com/resource/pubmed/chemical/Tec protein-tyrosine kinase
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| pubmed:status |
MEDLINE
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| pubmed:month |
Oct
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| pubmed:issn |
0022-2623
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| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
21
|
| pubmed:volume |
47
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
5405-17
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| pubmed:dateRevised |
2009-11-19
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| pubmed:meshHeading |
pubmed-meshheading:15481978-Amino Acid Sequence,
pubmed-meshheading:15481978-Aminoquinolines,
pubmed-meshheading:15481978-Animals,
pubmed-meshheading:15481978-Binding, Competitive,
pubmed-meshheading:15481978-Binding Sites,
pubmed-meshheading:15481978-Fluorescence Polarization,
pubmed-meshheading:15481978-Ligands,
pubmed-meshheading:15481978-Magnetic Resonance Spectroscopy,
pubmed-meshheading:15481978-Mice,
pubmed-meshheading:15481978-Models, Molecular,
pubmed-meshheading:15481978-Molecular Sequence Data,
pubmed-meshheading:15481978-Mutagenesis, Site-Directed,
pubmed-meshheading:15481978-Proline,
pubmed-meshheading:15481978-Protein-Tyrosine Kinases,
pubmed-meshheading:15481978-Quinazolines,
pubmed-meshheading:15481978-Sequence Alignment,
pubmed-meshheading:15481978-Structure-Activity Relationship,
pubmed-meshheading:15481978-src Homology Domains
|
| pubmed:year |
2004
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| pubmed:articleTitle |
Identification and specificity studies of small-molecule ligands for SH3 protein domains.
|
| pubmed:affiliation |
School of Molecular and Biomedical Science, The University of Adelaide, SA, 5005, Australia.
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|