The crystal structure of the Fab fragment of a rat monoclonal antibody against the main immunogenic region of the human muscle acetylcholine receptor

Maria Kontou, Demetres D. Leonidas, Efstratia H. Vatzaki, Panayiota Tsantili, Avgi Mamalaki, Nikos G. Oikonomakos, K. Ravi Acharya, Socrates J. Tzartos

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

The crystal structure of the Fab fragment of a rat monoclonal antibody, number 192, with a very high affinity (K(d) = 0.05 nM) for the main immunogenic region of the human muscle acetylcholine receptor (AChR), has been determined and refined to 2.4 Å resolution by X-ray crystallographic methods. The overall structure is similar to a Fab (NC6.8) from a murine antibody, used as a search model in molecular replacement. Structural comparisons with known antibody structures showed that the conformations of the hypervariable regions H1, H2, L1, L2, L3 of Fab 192 adopt the canonical structures 1, 1, 2, 1, and I, respectively. The surface of the antigen- binding site is relatively planar, as expected for an antibody against a large protein antigen, with an accessible area of 2865 Å2. Analysis of the electrostatic surface potential of the antigen-binding site shows that the bottom of the cleft formed in the center of the site appears to be negatively charged. The structure will be useful in the rational design of very high affinity humanized mutants of Fab 192, appropriate for therapeutic approaches of the model autoimmune disease myasthenia gravis.

Original languageEnglish
Pages (from-to)2389-2396
Number of pages8
JournalEuropean Journal of Biochemistry
Volume267
Issue number8
DOIs
Publication statusPublished - 4 May 2000

Keywords

  • Acetylcholine receptor
  • Antibody structure
  • X-ray crystallography

ASJC Scopus subject areas

  • Biochemistry

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