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Publication Abstract from PubMed

The engineering of catalytic function in antibodies requires precise information on their structure. Here, results are presented that show how the antibody domain structure affects its functionality. The previously designed organophosphate-metabolizing reactibody A17 has been re-engineered by replacing its constant kappa light chain by the lambda chain (A17lambda), and the X-ray structure of A17lambda has been determined at 1.95 A resolution. It was found that compared with A17kappa the active centre of A17lambda is displaced, stabilized and made more rigid owing to interdomain interactions involving the CDR loops from the VL and VH domains. These VL/VH domains also have lower mobility, as deduced from the atomic displacement parameters of the crystal structure. The antibody elbow angle is decreased to 126 degrees compared with 138 degrees in A17kappa. These structural differences account for the subtle changes in catalytic efficiency and thermodynamic parameters determined with two organophosphate ligands, as well as in the affinity for peptide substrates selected from a combinatorial cyclic peptide library, between the A17kappa and A17lambda variants. The data presented will be of interest and relevance to researchers dealing with the design of antibodies with tailor-made functions.

Role of kappa-->lambda light-chain constant-domain switch in the structure and functionality of A17 reactibody.,Ponomarenko N, Chatziefthimiou SD, Kurkova I, Mokrushina Y, Mokrushina Y, Stepanova A, Smirnov I, Avakyan M, Bobik T, Mamedov A, Mitkevich V, Belogurov A Jr, Fedorova OS, Dubina M, Golovin A, Lamzin V, Friboulet A, Makarov AA, Wilmanns M, Gabibov A Acta Crystallogr D Biol Crystallogr. 2014 Mar;70(Pt 3):708-19. doi:, 10.1107/S1399004713032446. Epub 2014 Feb 15. PMID:24598740^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.