Analysis of Fas-ligand interactions using a molecular model of the receptor-ligand interface

A molecular model of the complex between Fas and its ligand was generated t o better understand the location and putative effects of site-specific muta tions, analyze interactions at the Fas-FasL interface, and identify contact residues. The modeling study was conservative in the sense that regions in Fas and its ligand which could not be predicted with confidence were omitt ed from the model to ensure accuracy of the analysis. Using the model, it w as possible to map four of five N-linked glycosylation sites in Fas and Fas L and to study 10 of 11 residues previously identified by mutagenesis as im portant for binding. Interactions involving six of these residues could be analyzed in detail and their importance for binding was rationalized based on the model. The predicted structure of the Fas-FasL interface was consist ent with the experimentally established importance of these residues for bi nding. In addition, five previously not targeted residues were identified a nd predicted to contribute to binding via electrostatic interactions. Despi te its limitations, the study provided a much improved basis to understand the role of Fas and FasL residues for binding compared to previous residue mapping studies using only a molecular model of Fas.