Analyses of the complexation of cyclosporin A (CsA) by cyclophilin and the unusual properties of MeBm2t1-CsA lead us to propose a conformational change upon binding of the cyclophilin-CsA complex to the protein phosphatase, calcineurin.Structural analyses of natural products bound to their protein receptors can provide a detailed understanding of phenomena ranging from enzymatic catalysis to signal transduction. This is especially true when such analyses are combined with experimental results from other disciplines such as synthetic chemistry and molecular biology. In fact, it may be argued that the power of structure determination resides primarily in its ability to explain experimental data, and in doing so to facilitate the formulation of hypotheses which then can direct further experiments. In this report we describe a proposed model for the interactions in a multimeric complex involving two proteins and a natural product ligand. The model is based on crystallographic and NMR spectroscopic analyses of one of the proteins and its complex with the natural product, and on biochemical and biological data on a synthetic analog of the natural product.