Section: New Results
Modeling interfaces and contacts
Keywords: docking, scoring, interfaces, protein complexes, Voronoi diagrams, arrangements of balls.
Novel structural parameters of Ig-Ag complexes yield a quantitative description of interaction specificity and binding affinity
Participants : F. Cazals, S. Marillet.
In collaboration with P. Boudinot (INRA Jouy-en-Josas) and M-P. Lefranc (University of Montpellier 2).
Antibody-antigen complexes challenge our understanding, as analyses to date failed to unveil the key determinants of binding affinity and interaction specificity. In this work , we partially fill this gap based on novel quantitative analyses using two standardized databases, the IMGT/3Dstructure-DB and the structure affinity benchmark.
First, we introduce a statistical analysis of interfaces which enables the classification of ligand types (protein, peptide, chemical; cross-validated classification error of 9.6%), and yield binding affinity predictions of unprecedented accuracy (median absolute error of 0.878 kcal/mol). Second, we exploit the contributions made by CDRs in terms of position at the interface and atomic packing properties to show that in general, VH CDR3 and VL CDR3 make dominant contributions to the binding affinity, a fact also shown to be consistent with the enthalpy - entropy compensation associated with pre-configuration of CDR3. Our work suggests that the affinity prediction problem could be solved from databases of high resolution crystal structures of complexes with known affinity.
Anti-interleukin-6 signalling therapy rebalances the disrupted cytokine production of B cells from patients with active rheumatoid arthritis
Participants : F. Cazals, A. Lhéritier.
In collaboration with S. Fleischer (1. Charité University Medicine Berlin, Berlin, Germany), S. Ries (2. Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany), P. Shen (2.), G.R. Burmester (1.), T. Dörner (1.), S. Fillatreau (2., Institut Necker-Enfants Malades, Université Paris Descartes, IHP Hôpital Necker Enfants Malades).
Rheumatoid arthritis (RA) is associated with abnormal B cell-functions implicating antibody-dependent and -independent mechanisms. B cells have emerged as important cytokine-producing cells, and cytokines are well-known drivers of RA pathogenesis. To identify novel cytokine-mediated B-cell functions in RA, in this work , we comprehensively analysed the capacity of B cells from RA patients with an inadequate response to disease modifying anti-rheumatic drugs to produce cytokines in comparison with healthy donors (HD). RA B cells displayed a constitutively higher production of the pathogenic factors interleukin (IL)-8 and Gro-, while their production of several cytokines upon activation via the B cell receptor for antigen (BCR) was broadly suppressed, including a loss of the expression of the protective factor TRAIL, compared to HD B cells. These defects were partly erased after treatment with the IL-6-signalling inhibitor tocilizumab, indicating that abnormal IL-6 signalling contributed to these abnormalities. Noteworthy, the clinical response of individual patients to tocilizumab therapy could be predicted using the amounts of MIP- and -NGF produced by these patients’ B cells before treatment. Taken together, our study highlights hitherto unknown abnormal B-cell functions in RA patients, which are related to the unbalanced cytokine network, and are potentially relevant for RA pathogenesis and treatment.