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
Φόρτωση...
Ημερομηνία
Συγγραφείς
Kleinjung, J.
Petit, M. C.
Orlewski, P.
Mamalaki, A.
Tzartos, S. J.
Tsikaris, V.
Sakarellos-Daitsiotis, M.
Sakarellos, C.
Marraud, M.
Cung, M. T.
Τίτλος Εφημερίδας
Περιοδικό ISSN
Τίτλος τόμου
Εκδότης
Wiley
Περίληψη
Τύπος
Είδος δημοσίευσης σε συνέδριο
Είδος περιοδικού
peer reviewed
Είδος εκπαιδευτικού υλικού
Όνομα συνεδρίου
Όνομα περιοδικού
Biopolymers
Όνομα βιβλίου
Σειρά βιβλίου
Έκδοση βιβλίου
Συμπληρωματικός/δευτερεύων τίτλος
Περιγραφή
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. (C) 2000 John Wiley & Sons, Inc.
Περιγραφή
Λέξεις-κλειδιά
anti-acetylcholine receptor single chain fv antibody, homology modeling, molecular dynamics, myasthenia gravis, protein structure prediction, transferred nuclear overhauser effect spectroscopy, docking, crystallographic refinement, 3-dimensional structure, monoclonal-antibodies, hypervariable regions, alpha-subunit, recognition, residues, dynamics, docking, immunoglobulin
Θεματική κατηγορία
Παραπομπή
Σύνδεσμος
<Go to ISI>://000084994700001
http://onlinelibrary.wiley.com/store/10.1002/(SICI)1097-0282(200002)53:2<113::AID-BIP1>3.0.CO;2-J/asset/1_ftp.pdf?v=1&t=h0e0ly39&s=fa0e9f36aeab368a2a2f8fddcd598a45d8deb903
http://onlinelibrary.wiley.com/store/10.1002/(SICI)1097-0282(200002)53:2<113::AID-BIP1>3.0.CO;2-J/asset/1_ftp.pdf?v=1&t=h0e0ly39&s=fa0e9f36aeab368a2a2f8fddcd598a45d8deb903
Γλώσσα
en
Εκδίδον τμήμα/τομέας
Όνομα επιβλέποντος
Εξεταστική επιτροπή
Γενική Περιγραφή / Σχόλια
Ίδρυμα και Σχολή/Τμήμα του υποβάλλοντος
Πανεπιστήμιο Ιωαννίνων. Σχολή Θετικών Επιστημών. Τμήμα Χημείας