Linked Life Data

10823273

Source:http://linkedlifedata.com/resource/pubmed/id/10823273

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2000-9-5
pubmed:abstractText
Some monoclonal antibodies against plasminogen activator inhibitor-1 (PAI-1) are able to inhibit its reaction with its target proteinases. We have characterized the effect on PAI-1 of two monoclonal antibodies, Mab-2 and Mab-6, with overlapping epitopes in a sequence encompassing beta-strand 1A, alpha-helix F, and the loop connecting alpha-helix F and beta-strand 3A (the hF/s3A loop). Mab-2 reduced the inhibitory activity of wild type PAI-1 and almost totally abolished the inhibitory activity of a PAI-1 variant harboring an Ala substitution of Lys 325 (335 in the alpha1-proteinase inhibitor template residue numbering) in beta-strand 5A. In both cases, the neutralizing effect of the antibody was strongly potentiated by vitronectin. Mab-6 had no effect on wild type PAI-1, but reduced the inhibitory activity of the K325A variant. The effect of Mab-6 was not potentiated by vitronectin. With both Mab-2 and Mab-6, the neutralization of PAI-1 activity was associated with PAI-1 substrate behaviour. Mab-2, but not Mab-6, prevented vitronectin from rescuing PAI-1 from cold-induced substrate behaviour. We propose that the antibodies act by weakening the anchoring of alpha-helix F to the adjacent structures, resulting in an increased flexibility of beta-strand 5A and the hF/s3A loop and a changed conformational response to the binding of vitronectin in the alpha-helix E region. The potentiating effect of vitronectin on neutralization of PAI-1 by antibodies is a novel concept in the development of compounds for neutralizing PAI-1 in vivo.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0340-6245
pubmed:author
pubmed:issnType
Print
pubmed:volume
83
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
742-51
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:10823273-Amino Acid Motifs, pubmed-meshheading:10823273-Amino Acid Substitution, pubmed-meshheading:10823273-Antibodies, Monoclonal, pubmed-meshheading:10823273-Antibody Specificity, pubmed-meshheading:10823273-Epitopes, pubmed-meshheading:10823273-Humans, pubmed-meshheading:10823273-Hydrogen Bonding, pubmed-meshheading:10823273-Macromolecular Substances, pubmed-meshheading:10823273-Models, Molecular, pubmed-meshheading:10823273-Plasminogen Activator Inhibitor 1, pubmed-meshheading:10823273-Protein Binding, pubmed-meshheading:10823273-Protein Conformation, pubmed-meshheading:10823273-Serpins, pubmed-meshheading:10823273-Structure-Activity Relationship, pubmed-meshheading:10823273-Substrate Specificity, pubmed-meshheading:10823273-Temperature, pubmed-meshheading:10823273-Vitronectin
pubmed:year
2000
pubmed:articleTitle
Vitronectin and substitution of a beta-strand 5A lysine residue potentiate activity-neutralization of PA inhibitor-1 by monoclonal antibodies against alpha-helix F.
pubmed:affiliation
Department of Molecular and Structural Biology, Aarhus University, Denmark.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't