4uim
crystal structure of quinine-dependent Fab 314.3
Structural highlights
Publication Abstract from PubMedDrug-induced immune thrombocytopenia (DITP) is caused by antibodies that react with specific platelet membrane glycoproteins when the provoking drug is present. More than 100 drugs have been implicated as triggers for this condition, quinine being one of the most common. The cause of DITP in most cases appears to be a drug-induced antibody that binds to a platelet membrane glycoprotein only when drug is present. How soluble drug promotes binding of an otherwise non-reactive immunoglobulin to its target, leading to platelet destruction is uncertain, in part because of the difficulties of working with polyclonal human antibodies usually available only in small quantities. Recently, quinine-dependent murine monoclonal antibodies were developed that recognize a defined epitope on the beta-propeller domain of the platelet integrin alphaIIb-subunit (GPIIb) only when drug is present and closely mimic the behavior of antibodies found in human patients with quinine-induced thrombocytopenia in vitro and in vivo. Here, we demonstrate specific, high affinity binding of quinine to the complementarity-determining regions (CDR) of these antibodies and define in crystal structures the changes induced in the CDR by this interaction. Since in previous studies, no detectable binding of quinine to the target integrin could be demonstrated, the findings indicate that a hybrid paratope consisting of quinine and reconfigured antibody CDR plays a critical role in recognition of its target epitope by antibody and suggest that, in this type of drug-induced immunologic injury, the primary reaction involves binding of drug to antibody CDR, causing it to acquire specificity for a site on a platelet integrin. Structural basis for quinine-dependent antibody binding to platelet integrin alphaIIbbeta3.,Zhu J, Zhu J, Bougie DW, Aster RH, Springer TA Blood. 2015 Aug 17. pii: blood-2015-04-639351. PMID:26282540[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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