Role of  κ→λ light-chain constant-domain switch in the structure and functionality of A17 reactibody

Ponomarenko, N.; Chatziefthimiou, S.D.; Kurkova, I.; Mokrushina, Y.; Stepanova, A.; Smirnov, I.; Avakyan, M.; Bobik, T.; Mamedov, A.; Mitkevich, V.; Belogurov, A.; Fedorova, O.S.; Dubina, M.; Golovin, A.; Lamzin, V.; Friboulet, A.; Makarov, A.A.; Wilmanns, M.; Gabibov, A.

Авторы: Ponomarenko Natalia, Chatziefthimiou Spyros D., Kurkova Inna, Mokrushina Yuliana, Stepanova Anastasiya, Smirnov Ivan, Avakyan Marat, Bobik Tatyana, Mamedov Azad, Mitkevich Vladimir, Belogurov Alexey, Fedorova Olga S., Dubina Michael, Golovin Andrey, Lamzin Victor, Friboulet Alain, Makarov Alexander A., Wilmanns Matthias, Gabibov Alexander
Журнал: Acta Crystallographica Section D: Biological Crystallography
Том: 70
Номер: 3
Год издания: 2014
Издательство: Blackwell Publishing Inc.
Местоположение издательства: United Kingdom
Первая страница: 708
Последняя страница: 719
DOI: 10.1107/S1399004713032446
Аннотация: Abstract: 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 (A17[lambda]), and the X-ray structure of A17[lambda] has been determined at 1.95 Å resolution. It was found that compared with A17[kappa] the active centre of A17[lambda] 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° compared with 138° in A17[kappa]. 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 A17[kappa] and A17[lambda] variants. The data presented will be of interest and relevance to researchers dealing with the design of antibodies with tailor-made functions.
Добавил в систему: Головин Андрей Викторович

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Role of κ→λ light-chain constant-domain switch in the structure and functionality of A17 reactibodyстатья