1F3R

COMPLEX BETWEEN FV ANTIBODY FRAGMENT AND AN ANALOGUE OF THE MAIN IMMUNOGENIC REGION OF THE ACETYLCHOLINE RECEPTOR


Experimental Data Snapshot

  • Method: SOLUTION NMR
  • Conformers Calculated: 
  • Conformers Submitted: 
  • Selection Criteria: all calculated structures submitted 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

The third-dimensional structure of the complex between an Fv antibody fragment and an analogue of the main immunogenic region of the acetylcholine receptor: a combined two-dimensional NMR, homology, and molecular modeling approach.

Kleinjung, J.Petit, M.C.Orlewski, P.Mamalaki, A.Tzartos, S.J.Tsikaris, V.Sakarellos-Daitsiotis, M.Sakarellos, C.Marraud, M.Cung, M.T.

(2000) Biopolymers 53: 113-128

  • DOI: https://doi.org/10.1002/(SICI)1097-0282(200002)53:2<113::AID-BIP1>3.0.CO;2-J
  • Primary Citation of Related Structures:  
    1F3R

  • PubMed Abstract: 

    Binding of autoantibodies to the acetylcholine receptor (AChR) plays a major role in the autoimmune disease Myasthenia gravis (MG). In this paper, we propose a structure model of a putative immunocomplex that gives rise to the reduction of functional AChR molecules during the course of MG. The model complex consists of the [G(70), Nle(76)] decapeptide analogue of the main immunogenic region (MIR), representing the major antigenic epitope of AChR, and the single chain Fv fragment of monoclonal antibody 198, a potent MG autoantibody. The structure of the complexed decapeptide antigen [G(70), Nle(76)]MIR was determined using two-dimensional nmr, whereas the antibody structure was derived by means of homology modeling. The final complex was constructed using calculational docking and molecular dynamics. We termed this approach "directed modeling," since the known peptide structure directs the prestructured antibody binding site to its final conformation. The independently derived structures of the peptide antigen and antibody binding site already showed a high degree of surface complementarity after the initial docking calculation, during which the peptide was conformationally restrained. The docking routine was a soft algorithm, applying a combination of Monte Carlo simulation and energy minimization. The observed shape complementarity in the docking process suggested that the structure assessments already led to anti-idiotypic conformations of peptide antigen and antibody fragment. Refinement of the complex by dynamic simulation yielded improved surface adaptation by small rearrangements within antibody and antigen. The complex presented herein was analyzed in terms of antibody-antigen interactions, properties of contacting surfaces, and segmental mobility. The structural requirements for AChR complexation by autoantibodies were explored and compared with experimental data from alanine scans of the MIR peptides. The analysis revealed that the N-terminal loop of the peptide structure, which is indispensable for antibody recognition, aligns three hydrophobic groups in a favorable arrangement leading to the burial of 40% of the peptide surface in the binding cleft upon complexation. These data should be valuable in the rational design of an Fv mutant with much improved affinity for the MIR and AChR to be used in therapeutic approaches in MG.


  • Organizational Affiliation

    Laboratoire de Chimie-Physique Macromoleculaire, UMR 7568 CNRS-INPL, ENSIC, BP 451, 54001 Nancy Cedex, France.


Macromolecules

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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ACETYLCHOLINE RECEPTOR ALPHA10N/AMutation(s): 2 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
FV ANTIBODY FRAGMENT257Rattus norvegicusMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
NLE
Query on NLE
A
L-PEPTIDE LINKINGC6 H13 N O2LEU
Experimental Data & Validation

Experimental Data

  • Method: SOLUTION NMR
  • Conformers Calculated: 
  • Conformers Submitted: 
  • Selection Criteria: all calculated structures submitted 

Structure Validation

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Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2000-06-15
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2021-11-03
    Changes: Database references, Derived calculations