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Abstract
In several instances, a monoclonal antibody raised against a receptor ligand has been claimed to mimic the ligand receptor. Thus, a specific monoclonal antibody (Malpha2-3) raised against a short-chain toxin from snake was proposed to mimic the nicotinic acetylcholine receptor (AChR) (). Further confirming this mimicry, we show that (i) like AChR, Malpha2-3 elicits anti-AChR antibodies, which in turn elicit anti-toxin antibodies; and (ii) the region 106-122 of the alpha-chain of AChR shares 66% primary structure identity with complementarity-determining regions of Malpha2-3. Also, a mutational analysis of erabutoxin a reveals that the epitope recognized by Malpha2-3 consists of 10 residues, distributed within the three toxin loops. Eight of these residues also belong to the 10-residue epitope recognized by AChR, a result that offers an explanation as to the functional similarities between the receptor and the antibody. Strikingly, however, most of the residues common to the two epitopes contribute differentially to the energetic formation of the antibody-toxin and the receptor-toxin complexes. Together, the data suggest that the mimicry between AChR and Malpha2-3 is partial only.
Highlights
In several instances, a monoclonal antibody raised against a receptor ligand has been claimed to mimic the ligand receptor
A mutational analysis of erabutoxin a reveals that the epitope recognized by M␣2-3 consists of 10 residues, distributed within the three toxin loops
Preliminary studies based on the use of chemically modified toxin derivatives revealed that three toxin residues involved in the recognition of M␣2-3 were implicated in the acetylcholine receptor (AChR) binding site, indicating that the determinants recognized by AChR and M␣2-3 do overlap [1]
Summary
IDENTIFICATION OF SNAKE TOXIN DETERMINANTS RECOGNIZED BY THE ACETYLCHOLINE RECEPTOR AND AN ACETYLCHOLINE RECEPTOR-MIMICKING MONOCLONAL ANTIBODY*. Free energy calculations suggested that only a subset of the observed contacts contributes actively to the binding [12] In agreement with this view, mutational analyses of contacting areas in antibody-antigen or receptor-hormone complexes demonstrated the critical role of few residues only [13,14]. Having in hand data indicating functional and structural similarities between M␣2-3 and AChR, we delineated the epitope recognized by M␣2-3 on the surface of Ea, on the basis of a mutational approach, using a large set of toxin mutants. We compared this epitope with the previously identified de-. The data reported in the present study clarify the molecular basis associated with the notion of mimicry of a receptor by an antibody
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