ArticleThe Journal of biological chemistry2016
Conformational Destabilization of Immunoglobulin G Increases the Low pH Binding Affinity with the Neonatal Fc Receptor.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 42 citations in OpenAlex.
- Comparative assessment of tissue cross-reactivity and pharmacokinetic half-life of malaria monoclonal antibodies.Frontiers in immunology · 2026Article
- Enhancement of Protein-Protein Interactions by Destabilizing Mutations Revealed by HDX-MS.Biomolecules · 2025Review
- Identification of a direct interaction between the Fab domains of IgG antibodies and human FcRn upon IgG-FcRn complex formation.Communications biology · 2025Article
- Interpretation of Hydrogen/Deuterium Exchange Mass Spectrometry.Journal of the American Society for Mass Spectrometry · 2024Article
- Harnessing Fc/FcRn Affinity Data from Patents with Different Machine Learning Methods.International journal of molecular sciences · 2023Article
- Design of a chimeric ACE-2/Fc-silent fusion protein with ultrahigh affinity and neutralizing capacity for SARS-CoV-2 variants.Antibody therapeutics · 2023Article
- Improving Antibody Therapeutics by Manipulating the Fc Domain: Immunological and Structural Considerations.Annual review of biomedical engineering · 2022Review
- Advances in Hydrogen/Deuterium Exchange Mass Spectrometry and the Pursuit of Challenging Biological Systems.Chemical reviews · 2022Review
- Human IgG1 Fc pH-dependent optimization from a constant pH molecular dynamics simulation analysis.RSC advances · 2020Article
- An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.Nature communications · 2019Article
- Hybrid mass spectrometry methods reveal lot-to-lot differences and delineate the effects of glycosylation on the tertiary structure of Herceptin®.Chemical science · 2019Article
- Maternal immunity and antibodies to dengue virus promote infection and Zika virus-induced microcephaly in fetuses.Science advances · 2019Article
- Introduction of the YTE mutation into the non-immunogenic HIV bnAb PGT121 induces anti-drug antibodies in macaques.PloS one · 2019Article
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- The Area Between Exchange Curves as a Measure of Conformational Differences in Hydrogen-Deuterium Exchange Mass Spectrometry Studies.Journal of the American Society for Mass Spectrometry · 2017Article
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Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Crystallographic evidence suggests that the pH-dependent affinity of IgG molecules for the neonatal Fc receptor (FcRn) receptor primarily arises from salt bridges involving IgG histidine residues, resulting in moderate affinity at mildly acidic conditions. However, this view does not explain the diversity in affinity found in IgG variants, such as the YTE mutant (M252Y,S254T,T256E), which increases affinity to FcRn by up to 10×. Here we compare hydrogen exchange measurements at pH 7.0 and pH 5.5 with and without FcRn bound with surface plasmon resonance estimates of dissociation constants and FcRn affinity chromatography. The combination of experimental results demonstrates that differences between an IgG and its cognate YTE mutant vary with their pH-sensitive dynamics prior to binding FcRn. The conformational dynamics of these two molecules are nearly indistinguishable upon binding FcRn. We present evidence that pH-induced destabilization in the CH2/3 domain interface of IgG increases binding affinity by breaking intramolecular H-bonds and increases side-chain adaptability in sites that form intermolecular contacts with FcRn. Our results provide new insights into the mechanism of pH-dependent affinity in IgG-FcRn interactions and exemplify the important and often ignored role of intrinsic conformational dynamics in a protein ligand, to dictate affinity for biologically important receptors.
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