Source:http://linkedlifedata.com/resource/pubmed/id/15865430
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
18
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| pubmed:dateCreated |
2005-5-3
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| pubmed:abstractText |
A synthetic analogue of the tripeptide hemiasterlin, designated HTI-286, depolymerizes microtubules, is a poor substrate for P-glycoprotein, and inhibits the growth of paclitaxel-resistant tumors in xenograft models. Two radiolabeled photoaffinity analogues of HTI-286, designated 4-benzoyl-N,beta,beta-trimethyl-l-phenylalanyl-N(1)-[(1S,2E)-3-carboxy-1-isopropylbut-2-enyl]-N(1),3-dimethyl-l-valinamide (probe 1) and N,beta,beta-trimethyl-l-phenylalanyl-4-benzoyl-N-[(1S,2E)-3-carboxy-1-isopropyl-2-butenyl]-N,beta,beta-trimethyl-l-phenylalaninamide (probe 2), were made to help identify HTI-286 binding sites in tubulin. HTI-286, probe 1, and probe 2 had similar affinities for purified tubulin [apparent K(D(app)) = 0.2-1.1 microM], inhibited polymerization of purified tubulin approximately 80%, and were potent inhibitors of cell growth (IC(50) = 1.0-22 nM). Both radiolabeled probes labeled exclusively alpha-tubulin. Labeling by [(3)H]probe 1 was inhibited by probe 1, HTI-286, vinblastine, or dolastatin 10 (another peptide antimitotic agent that depolymerizes microtubules) but was either unaffected or enhanced (at certain temperatures) by colchicine or paclitaxel. [(3)H]Probe 1 also labeled exclusively tubulin in cytosolic extracts of whole cells. The major, if not exclusive, contact site for probe 1 was mapped to residues 314-339 of alpha-tubulin and corresponds to the sheet 8 and helix 10 region. This region is known to (1) have longitudinal interactions with beta-tubulin across the interdimer interface, (2) have lateral interactions with adjacent protofilaments, and (3) contact the N-terminal region of stathmin, a protein that induces depolymerization of tubulin. Binding of probe 1 to this region may alter the conformation of tubulin outside the labeling domain, since enzymatic removal of the C-terminus of only alpha-tubulin by subtilisin after, but not before, photolabeling is blocked by probe 1. These results suggest that hemiasterlin is in close contact with alpha-tubulin and may span the interdimer interface so that it contacts the vinblastine- and dolastatin 10-binding sites believed to be in beta-tubulin. In addition, we speculate that antimitotic peptides mimic the interaction of stathmin with tubulin.
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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/Depsipeptides,
http://linkedlifedata.com/resource/pubmed/chemical/Growth Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Guanosine Triphosphate,
http://linkedlifedata.com/resource/pubmed/chemical/HTI-286,
http://linkedlifedata.com/resource/pubmed/chemical/Oligopeptides,
http://linkedlifedata.com/resource/pubmed/chemical/Photoaffinity Labels,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Subunits,
http://linkedlifedata.com/resource/pubmed/chemical/Tubulin,
http://linkedlifedata.com/resource/pubmed/chemical/Tubulin Modulators,
http://linkedlifedata.com/resource/pubmed/chemical/Vinblastine,
http://linkedlifedata.com/resource/pubmed/chemical/dolastatin 10,
http://linkedlifedata.com/resource/pubmed/chemical/hemiasterlin
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| pubmed:status |
MEDLINE
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| pubmed:month |
May
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| pubmed:issn |
0006-2960
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| pubmed:author |
pubmed-author:Ayral-KaloustianSemiramisS,
pubmed-author:BeyerCarlC,
pubmed-author:GreenbergerLee MLM,
pubmed-author:HariMalathiM,
pubmed-author:KaplanJoshuaJ,
pubmed-author:KrishnamurthyGirijaG,
pubmed-author:LoganzoFrankF,
pubmed-author:MayMichael KMK,
pubmed-author:MinnickAlbert AAAJr,
pubmed-author:MustoSylviaS,
pubmed-author:NunesMariaM,
pubmed-author:QiuYongchangY,
pubmed-author:ShiCelineC,
pubmed-author:WootersJosephJ,
pubmed-author:ZaskArieA
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| pubmed:issnType |
Print
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| pubmed:day |
10
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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 |
6844-57
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| pubmed:dateRevised |
2007-11-15
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| pubmed:meshHeading |
pubmed-meshheading:15865430-Amino Acid Sequence,
pubmed-meshheading:15865430-Animals,
pubmed-meshheading:15865430-Binding, Competitive,
pubmed-meshheading:15865430-Cattle,
pubmed-meshheading:15865430-Cytosol,
pubmed-meshheading:15865430-Depsipeptides,
pubmed-meshheading:15865430-Growth Inhibitors,
pubmed-meshheading:15865430-Guanosine Triphosphate,
pubmed-meshheading:15865430-HeLa Cells,
pubmed-meshheading:15865430-Humans,
pubmed-meshheading:15865430-KB Cells,
pubmed-meshheading:15865430-Molecular Sequence Data,
pubmed-meshheading:15865430-Oligopeptides,
pubmed-meshheading:15865430-Peptide Mapping,
pubmed-meshheading:15865430-Photoaffinity Labels,
pubmed-meshheading:15865430-Protein Binding,
pubmed-meshheading:15865430-Protein Subunits,
pubmed-meshheading:15865430-Tubulin,
pubmed-meshheading:15865430-Tubulin Modulators,
pubmed-meshheading:15865430-Vinblastine
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| pubmed:year |
2005
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| pubmed:articleTitle |
Two photoaffinity analogues of the tripeptide, hemiasterlin, exclusively label alpha-tubulin.
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| pubmed:affiliation |
Oncology Research, Chemical and Screening Sciences, Radiosynthesis Group, and Bioorganic Enzymology, Wyeth Research, 401 North Middletown Road, Pearl River, New York 10965, USA. nunesm@wyeth.com
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| pubmed:publicationType |
Journal Article
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