Structure and kinetics of a transient antibody binding intermediate reveal a kinetic discrimination mechanism in antigen recognition.

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  • Author(s): James LC;James LC; Tawfik DS
  • Source:
    Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2005 Sep 06; Vol. 102 (36), pp. 12730-5. Date of Electronic Publication: 2005 Aug 29.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0027-8424 (Print) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : National Academy of Sciences
    • Subject Terms:
      Antibody Specificity*; Antigens/*chemistry ; Antigens/*immunology ; Immunoglobulin E/*chemistry ; Immunoglobulin E/*immunology; Anthracenes/chemistry ; Binding Sites ; Crystallography, X-Ray ; Hydrogen Bonding ; Isomerism ; Kinetics ; Ligands ; Models, Molecular ; Protein Binding ; Protein Structure, Quaternary
    • Abstract:
      Induced fit is a predominant phenomenon in protein-ligand interactions, yet it is invariably attributed without establishing the existence, let alone the structure, of the initial, low-affinity encounter complex. We determined the crystal structure of the encounter complex on the pathway of ligand binding by IgE antibody SPE7. We show that this complex is formed by a wide range of ligands that initially bind with identical affinity. Nonspecific ligands rapidly dissociate, whereupon the antibody isomerizes to a nonbinding isomer. Specific ligand complexes, however, slowly isomerize to give a high-affinity complex. This isomerization involves backbone and side-chain rearrangements of up to 14 A and the formation of specific hydrogen bonds. The postbinding conformational switch, combined with the prebinding isomerization to an energetically favorable nonbinding isomer, results in a "kinetic discrimination" mechanism that mediates selective binding, by a factor of >10(3), between highly related ligands that initially bind with the same affinity. This model may apply to proteins that bind multiple ligands in a specific manner or other proteins that, although capable of binding many ligands, are activated by only a few.
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    • Grant Information:
      United Kingdom WT_ Wellcome Trust
    • Molecular Sequence:
      PDB 2BJM
    • Accession Number:
      0 (Anthracenes)
      0 (Antigens)
      0 (Ligands)
      37341-29-0 (Immunoglobulin E)
      FP0FJ7K744 (anthrone)
    • Publication Date:
      Date Created: 20050901 Date Completed: 20051101 Latest Revision: 20240412
    • Publication Date:
      20240412
    • Accession Number:
      PMC1200256
    • Accession Number:
      10.1073/pnas.0500909102
    • Accession Number:
      16129832