Small angle X-ray scattering (SAXS) was applied to the binding of the immunosuppressant drug cyclosporin-A to the protein calmodulin. Guinier analysis of the SAXS profiles yielded a radius of gyration, R(g), of 19.7 +/- 0.3 Angstrom for the native protein and 16.9 +/- 0.3 Angstrom for the drug/ protein complex. Maximum entropy (maxent) methods of data analysis were used to calculate the distance distribution function, p(r). From this analysis, the R(g) for the native protein is 20.9 +/-0.1 Angstrom and that for the complex 16.7 +/- 0.1 Angstrom. The measured SAXS profiles and the derived p(r) for calmodulin agree with profiles calculated from the crystallographic structure of calmodulin. Major structural changes are induced in calmodulin on binding cyclosporin-A. A model consistent with the observed seattering profiles is an ellipsoid with major axes 55 and 36 Angstrom. Molecular modeling of the calmodulin molecule suggests that bond rotation in the flexible alpha-helix linker region produces models consistent with the above observations. (C) 1994 Academic Press, Inc.