Linked Life Data

19748896

Source:http://linkedlifedata.com/resource/pubmed/id/19748896

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
45
pubmed:dateCreated
2009-11-2
pubmed:abstractText
Interactions between Bcl-2 homology-3 (BH3)-only proteins and their pro-survival Bcl-2 family binding partners initiate the intrinsic apoptosis pathway. These interactions are mediated by a short helical motif, the BH3 domain, on the BH3-only protein, which inserts into a hydrophobic groove on the pro-survival molecule. To identify novel peptidic ligands that bind Mcl-1, a pro-survival protein relative of Bcl-2, both human and mouse Mcl-1 were screened against large randomized phage-displayed peptide libraries. We identified a number of 16-mer peptides with sub-micromolar affinity that were highly selective for Mcl-1, as well as being somewhat selective for the species of Mcl-1 (human or mouse) against which the library was panned. Interestingly, these sequences all strongly resembled natural BH3 domain sequences. By switching residues within the best of the human Mcl-1-binding sequences, or extending beyond the core sequence identified, we were able to alter the pro-survival protein interaction profile of this peptide such that it now bound all members tightly and was a potent killer when introduced into cells. Introduction of an amide lock constraint within this sequence also increased its helicity and binding to pro-survival proteins. These data provide new insights into the determinants of BH3 domain:pro-survival protein affinity and selectivity.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
1083-351X
pubmed:author
pubmed:issnType
Electronic
pubmed:day
6
pubmed:volume
284
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
31315-26
pubmed:dateRevised
2010-11-9
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
Novel Bcl-2 homology-3 domain-like sequences identified from screening randomized peptide libraries for inhibitors of the pro-survival Bcl-2 proteins.
pubmed:affiliation
Walter and Eliza Hall Institute of Medical Research, 1G Royal Pde., Parkville, Victoria 3052, Australia.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't