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      In-depth analysis of subclass-specific conformational preferences of IgG antibodies

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          Abstract

          An extended analysis of structural ensembles obtained from small-angle X-ray scattering data reveals subclass-specific conformational preferences of IgG antibodies, which are largely determined by the hinge-region structure.

          Abstract

          IgG subclass-specific differences in biological function and in vitro stability are often referred to variations in the conformational flexibility, while this flexibility has rarely been characterized. Here, small-angle X-ray scattering data from IgG1, IgG2 and IgG4 antibodies, which were designed with identical variable regions, were thoroughly analysed by the ensemble optimization method. The extended analysis of the optimized ensembles through shape clustering reveals distinct subclass-specific conformational preferences, which provide new insights for understanding the variations in physical/chemical stability and biological function of therapeutic antibodies. Importantly, the way that specific differences in the linker region correlate with the solution structure of intact antibodies is revealed, thereby visualizing future potential for the rational design of antibodies with designated physicochemical properties and tailored effector functions. In addition, this advanced computational approach is applicable to other flexible multi-domain systems and extends the potential for investigating flexibility in solutions of macromolecules by small-angle X-ray scattering.

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          Author and article information

          Journal
          IUCrJ
          IUCrJ
          IUCrJ
          IUCrJ
          International Union of Crystallography
          2052-2525
          01 January 2015
          01 January 2015
          01 January 2015
          : 2
          : Pt 1 ( publisher-idID: m150100 )
          : 9-18
          Affiliations
          [a ]Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, Copenhagen 2100, Denmark
          [b ]Biopharmaceuticals Research Unit, Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Måløv, Denmark
          [c ]Biopharmaceuticals Research Unit, Novo Nordisk A/S, Life Science Park Road 29, Beijing 102206, People’s Republic of China
          Author notes
          Article
          tj5007 IUCRAJ S205225251402209X
          10.1107/S205225251402209X
          4285876
          25610623
          d7d95a8c-7562-49f4-8589-b606bc1a2738
          © Xinsheng Tian et al. 2015

          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.

          History
          : 22 August 2014
          : 07 October 2014
          Categories
          Research Papers

          igg antibody,solution conformation,small-angle x-ray scattering (saxs),structure modelling,shape clustering

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