Linked Life Data

17311379

Source:http://linkedlifedata.com/resource/pubmed/id/17311379

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
2007-3-7
pubmed:abstractText
While arsenic(III) compounds can exert profound toxicological and pharmacological effects, their modes of action and, in particular, the structural consequences of their binding to cysteinyl side chains in proteins, remain poorly understood. To gain an understanding of how arsenic binding influences beta-structure, pairs of cysteines were introduced into a model monomeric beta-hairpin to yield a family of peptides such that coordination occurs either across the strands or within the same strand of the beta-hairpin. Circular dichroism, NMR, UV-vis spectroscopy, and rapid-reaction studies were used to characterize the binding of monomethylarsonous acid or p-succinylamidephenyl arsenoxide (PSAO) to these peptides. Placement of cysteines at non-hydrogen bond (NHB) positions across the beta-hairpin, such that they occupy the same face of the sheet, was found to enhance the structure as assessed by CD. Cross-strand cysteine residues that project on opposite faces close to the termini of the hairpin can still bind arsenic tightly and show modestly increased beta-sheet content. NMR and modeling studies suggest that arsenic can be accommodated at this locus without disrupting the core interactions stabilizing the turn. However, As(III) binding to nonopposed cysteines, or to cysteines at HB and NHB positions along one strand of the hairpin, caused loss of structure. UV-vis titrations show that all these hairpin peptides bind PSAO stoichiometrically with K(d) values from 13 to 106 nM. Further, binding is moderately rapid, with second-order rate constants for association of 10,000-22,000 M(-1) s(-)1 irrespective of the placement of the cysteines within the hairpin and the consequent extent of structural reorganization required as a result of binding. These studies complement recent work with alpha-helices and further demonstrate that capture of a pair of thiols by As(III) may result in significant changes in local secondary structure in the protein targets of these potent bioactive agents.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0002-7863
pubmed:author
pubmed:issnType
Print
pubmed:day
14
pubmed:volume
129
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2981-8
pubmed:dateRevised
2007-12-3
pubmed:meshHeading
pubmed:year
2007
pubmed:articleTitle
Effects of As(III) binding on beta-hairpin structure.
pubmed:affiliation
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716-2522, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural