Antibody-protein binding and conformational changes : identifying allosteric signalling pathways to engineer a better effector response

Al Qaraghuli, Mohammed M. and Kubiak-Ossowska, Karina and Ferro, Valerie A. and Mulheran, Paul A. (2020) Antibody-protein binding and conformational changes : identifying allosteric signalling pathways to engineer a better effector response. Scientific Reports, 10. p. 13696. 13696. ISSN 2045-2322 (https://doi.org/10.1038/s41598-020-70680-0)

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Abstract

Numerous monoclonal antibodies have been developed successfully for the treatment of various diseases. Nevertheless, the development of biotherapeutic antibodies is complex, expensive, and time-consuming, and to facilitate this process, careful structural analysis beyond the antibody binding site is required to develop a more efficacious antibody. In this work, we focused on protein antigens, since they induce the largest antibody changes, and provide interesting cases to compare and contrast. The structures of 15 anti-protein antibodies were analysed to compare the antigen-bound/unbound forms. Surprisingly, three different classes of binding-induced changes were identified. In class (B1), the antigen binding fragment distorted significantly, and we found changes in the loop region of the heavy chain’s constant domain; this corresponds well with expected allosteric movements. In class (B2), we found changes in the same loop region without the overall distortion. In class (B3), these changes did not present, and only local changes at the complementarity determining regions were found. Consequently, structural analysis of antibodies is crucial for therapeutic development. Careful evaluation of allosteric movements must be undertaken to develop better effector responses, especially during the transformation of these antibodies from small fragments at the discovery stage to full antibodies at the subsequent development stages.

ORCID iDs

Al Qaraghuli, Mohammed M. ORCID logoORCID: https://orcid.org/0000-0003-1823-6671, Kubiak-Ossowska, Karina, Ferro, Valerie A. ORCID logoORCID: https://orcid.org/0000-0003-1967-3603 and Mulheran, Paul A. ORCID logoORCID: https://orcid.org/0000-0002-9469-8010;
CORE (COnnecting REpositories)