|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
6802
|
|
pubmed:dateCreated |
2000-10-19
|
|
pubmed:abstractText |
Protein kinases have proved to be largely resistant to the design of highly specific inhibitors, even with the aid of combinatorial chemistry. The lack of these reagents has complicated efforts to assign specific signalling roles to individual kinases. Here we describe a chemical genetic strategy for sensitizing protein kinases to cell-permeable molecules that do not inhibit wild-type kinases. From two inhibitor scaffolds, we have identified potent and selective inhibitors for sensitized kinases from five distinct subfamilies. Tyrosine and serine/threonine kinases are equally amenable to this approach. We have analysed a budding yeast strain carrying an inhibitor-sensitive form of the cyclin-dependent kinase Cdc28 (CDK1) in place of the wild-type protein. Specific inhibition of Cdc28 in vivo caused a pre-mitotic cell-cycle arrest that is distinct from the G1 arrest typically observed in temperature-sensitive cdc28 mutants. The mutation that confers inhibitor-sensitivity is easily identifiable from primary sequence alignments. Thus, this approach can be used to systematically generate conditional alleles of protein kinases, allowing for rapid functional characterization of members of this important gene family.
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/CDC28 Protein Kinase, S cerevisiae,
http://linkedlifedata.com/resource/pubmed/chemical/Carbazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/FUS3 protein, S cerevisiae,
http://linkedlifedata.com/resource/pubmed/chemical/Fungal Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Indole Alkaloids,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Saccharomyces cerevisiae Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/phosphoprotein phosphatase...,
http://linkedlifedata.com/resource/pubmed/chemical/staurosporine aglycone
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Sep
|
|
pubmed:issn |
0028-0836
|
|
pubmed:author |
pubmed-author:BishopA CAC,
pubmed-author:BlethrowJJ,
pubmed-author:GrayN SNS,
pubmed-author:MatheosD PDP,
pubmed-author:MorganD ODO,
pubmed-author:PetschD TDT,
pubmed-author:RoseM DMD,
pubmed-author:SchultzP GPG,
pubmed-author:ShimizuEE,
pubmed-author:ShokatK MKM,
pubmed-author:TsienJ ZJZ,
pubmed-author:UbersaxJ AJA,
pubmed-author:WoodJ LJL
|
|
pubmed:issnType |
Print
|
|
pubmed:day |
21
|
|
pubmed:volume |
407
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
395-401
|
|
pubmed:dateRevised |
2011-11-17
|
|
pubmed:meshHeading |
pubmed-meshheading:11014197-Alleles,
pubmed-meshheading:11014197-Amino Acid Sequence,
pubmed-meshheading:11014197-CDC28 Protein Kinase, S cerevisiae,
pubmed-meshheading:11014197-Carbazoles,
pubmed-meshheading:11014197-Cell Cycle,
pubmed-meshheading:11014197-Enzyme Inhibitors,
pubmed-meshheading:11014197-Fungal Proteins,
pubmed-meshheading:11014197-Gene Expression,
pubmed-meshheading:11014197-Humans,
pubmed-meshheading:11014197-Indole Alkaloids,
pubmed-meshheading:11014197-Mitogen-Activated Protein Kinases,
pubmed-meshheading:11014197-Molecular Sequence Data,
pubmed-meshheading:11014197-Mutagenesis,
pubmed-meshheading:11014197-Protein Kinase Inhibitors,
pubmed-meshheading:11014197-Protein Kinases,
pubmed-meshheading:11014197-Protein Structure, Tertiary,
pubmed-meshheading:11014197-Proteins,
pubmed-meshheading:11014197-Saccharomyces cerevisiae,
pubmed-meshheading:11014197-Saccharomyces cerevisiae Proteins,
pubmed-meshheading:11014197-Sequence Homology, Amino Acid,
pubmed-meshheading:11014197-Transcription, Genetic
|
|
pubmed:year |
2000
|
|
pubmed:articleTitle |
A chemical switch for inhibitor-sensitive alleles of any protein kinase.
|
|
pubmed:affiliation |
Department of Chemistry, Princeton University, New Jersey 08544, USA.
|
|
pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, Non-U.S. Gov't
|
