Linked Life Data

11559698

Source:http://linkedlifedata.com/resource/pubmed/id/11559698

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
48
pubmed:dateCreated
2001-11-23
pubmed:abstractText
The serpin plasminogen activator inhibitor type 1 (PAI-1) plays a regulatory role in various physiological processes (e.g. fibrinolysis and pericellular proteolysis) and forms a potential target for therapeutic interventions. In this study we identified the epitopes of three PAI-1 inhibitory monoclonal antibodies (MA-44E4, MA-42A2F6, and MA-56A7C10). Differential cross-reactivities of these monoclonals with PAI-1 from different species and sequence alignments between these PAI-1s, combined with the three-dimensional structure, revealed several charged residues as possible candidates to contribute to the respective epitopes. The production, characterization, and subsequent evaluation of a variety of alanine mutants using surface plasmon resonance revealed that the residues His(185), Arg(186), and Arg(187) formed the major sites of interaction for MA-44E4. In contrast, the epitopes of MA-42A2F6 and MA-56A7C10 were found to be conformational. The epitope of MA-42A2F6 comprises residues Lys(243) and Glu(350), whereas the epitope of MA-56A7C10 comprises residues Glu(242), Lys(243), Glu(244), Glu(350), Asp(355), and Arg(356). The participation of Glu(350), Asp(355), and Arg(356) provides a molecular explanation for the differential exposure of this epitope in the different conformations of PAI-1 and for the effect of these antibodies on the kinetics of the formation of the initial PAI-1-proteinase complexes. The localization of the epitopes of MA-44E4, MA42A2F6, and MA-56A7C10 elucidates two previously unidentified molecular mechanisms to modulate PAI-1 activity and opens new perspectives for the rational development of PAI-1 neutralizing compounds.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
30
pubmed:volume
276
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
44912-8
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed-meshheading:11559698-Alanine, pubmed-meshheading:11559698-Amino Acid Sequence, pubmed-meshheading:11559698-Animals, pubmed-meshheading:11559698-Antibodies, Monoclonal, pubmed-meshheading:11559698-Arginine, pubmed-meshheading:11559698-Aspartic Acid, pubmed-meshheading:11559698-Binding Sites, pubmed-meshheading:11559698-DNA, pubmed-meshheading:11559698-Epitopes, pubmed-meshheading:11559698-Glutamic Acid, pubmed-meshheading:11559698-Histidine, pubmed-meshheading:11559698-Humans, pubmed-meshheading:11559698-Kinetics, pubmed-meshheading:11559698-Lysine, pubmed-meshheading:11559698-Mice, pubmed-meshheading:11559698-Models, Molecular, pubmed-meshheading:11559698-Molecular Sequence Data, pubmed-meshheading:11559698-Mutation, pubmed-meshheading:11559698-Plasminogen Activator Inhibitor 1, pubmed-meshheading:11559698-Protein Binding, pubmed-meshheading:11559698-Protein Conformation, pubmed-meshheading:11559698-Protein Structure, Tertiary, pubmed-meshheading:11559698-Rats, pubmed-meshheading:11559698-Sequence Homology, Amino Acid, pubmed-meshheading:11559698-Surface Plasmon Resonance, pubmed-meshheading:11559698-Swine, pubmed-meshheading:11559698-Time Factors
pubmed:year
2001
pubmed:articleTitle
The distal hinge of the reactive site loop and its proximity: a target to modulate plasminogen activator inhibitor-1 activity.
pubmed:affiliation
Laboratory for Pharmaceutical Biology and Phytopharmacology, Faculty of Pharmaceutical Sciences, Katholieke Universiteit Leuven, Belgium.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't