Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2006-5-22
pubmed:abstractText
Phosphoinositide 3-kinases (PI3-Ks) are an important emerging class of drug targets, but the unique roles of PI3-K isoforms remain poorly defined. We describe here an approach to pharmacologically interrogate the PI3-K family. A chemically diverse panel of PI3-K inhibitors was synthesized, and their target selectivity was biochemically enumerated, revealing cryptic homologies across targets and chemotypes. Crystal structures of three inhibitors bound to p110gamma identify a conformationally mobile region that is uniquely exploited by selective compounds. This chemical array was then used to define the PI3-K isoforms required for insulin signaling. We find that p110alpha is the primary insulin-responsive PI3-K in cultured cells, whereas p110beta is dispensable but sets a phenotypic threshold for p110alpha activity. Compounds targeting p110alpha block the acute effects of insulin treatment in vivo, whereas a p110beta inhibitor has no effect. These results illustrate systematic target validation using a matrix of inhibitors that span a protein family.
pubmed:grant
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0092-8674
pubmed:author
pubmed:issnType
Print
pubmed:day
19
pubmed:volume
125
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
733-47
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed-meshheading:16647110-Adipose Tissue, pubmed-meshheading:16647110-Animals, pubmed-meshheading:16647110-Binding Sites, pubmed-meshheading:16647110-Crystallography, X-Ray, pubmed-meshheading:16647110-Enzyme Inhibitors, pubmed-meshheading:16647110-Female, pubmed-meshheading:16647110-Glucose, pubmed-meshheading:16647110-Humans, pubmed-meshheading:16647110-Insulin, pubmed-meshheading:16647110-Insulin Receptor Substrate Proteins, pubmed-meshheading:16647110-Isoenzymes, pubmed-meshheading:16647110-Mice, pubmed-meshheading:16647110-Models, Molecular, pubmed-meshheading:16647110-Molecular Structure, pubmed-meshheading:16647110-Muscle Fibers, Skeletal, pubmed-meshheading:16647110-Phosphatidylinositol 3-Kinases, pubmed-meshheading:16647110-Phosphoproteins, pubmed-meshheading:16647110-Signal Transduction
pubmed:year
2006
pubmed:articleTitle
A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling.
pubmed:affiliation
Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural