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

Catalytic antibody variants with κ and λ light-chain constant domains show differences in their crystal structures which lead to subtle changes in catalytic efficiency and thermodynamic parameters as well as in their affinity for peptide substrates. 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 κ light chain by the λ chain (A17λ), and the X-ray structure of A17λ has been determined at 1.95 Å resolution. It was found that compared with A17κ the active centre of A17λ is displaced, stabilized and made more rigid owing to interdomain interactions involving the CDR loops from the V{sub L} and V{sub H} domains. These V{sub L}/V{sub H} 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 A17κ. 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,more » between the A17κ and A17λ variants. The data presented will be of interest and relevance to researchers dealing with the design of antibodies with tailor-made functions.« less
Authors:
 [1] ;  [2] ; ; ; ; ; ; ; ;  [1] ;  [3] ;  [1] ;  [4] ;  [5] ;  [6] ;  [7] ;  [2] ;  [8] ;  [3] ;  [2] more »;  [1] ;  [4] ;  [4] « less
  1. Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow 117871 (Russian Federation)
  2. European Molecular Biology Laboratory, Hamburg Unit, c/o DESY, Notkestrasse 85, 22603 Hamburg (Germany)
  3. Russian Academy of Sciences, Moscow 119991 (Russian Federation)
  4. (Russian Federation)
  5. Russian Academy of Sciences, Novosibirsk 630090 (Russian Federation)
  6. St Petersburg Academic University, St Petersburg 194021 (Russian Federation)
  7. Lomonosov Moscow State University, Moscow 119991 (Russian Federation)
  8. Centre National de la Recherche Scientifique, 60205 Compiègne (France)
Publication Date:
OSTI Identifier:
22347784
Resource Type:
Journal Article
Resource Relation:
Journal Name: Acta Crystallographica. Section D: Biological Crystallography; Journal Volume: 70; Journal Issue: Pt 3; Other Information: PMCID: PMC3949517; PMID: 24598740; PUBLISHER-ID: wd5216; OAI: oai:pubmedcentral.nih.gov:3949517; Copyright (c) Ponomarenko et al. 2014; This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
Denmark
Language:
English
Subject:
75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY; AFFINITY; ANTIBODIES; ATOMS; CRYSTAL STRUCTURE; CRYSTALS; DESIGN; DOMAIN STRUCTURE; EFFICIENCY; INTERACTIONS; LIGANDS; MOBILITY; RESOLUTION; SUBSTRATES; VISIBLE RADIATION