Elucidation of the steric bases of anticancer activities of interferons through a combined approach by X-ray crystal structure analyzes and protein engineering.

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1) Set-up of the X-ray diffractometer system.The "recording device for diffracted X-ray beam", whcih was purchased by the present grant, completed the set-up of the two-dimensional X-ray diffraactometer using Imaging Plates.2) Set-up of the computer graphics system.The "CPU-upgrading system" purchased by the present grant, was succesfully incorporated into the existing system extensively upgrading its performance.3) Refinement of the crystal structure of murine interferon-betaUsing the systems 1) and 2) above, the structure has been refined at 2.15 A resolution to an R-factor of 19.1%. Extensive modification was found necessary for the A-Helix portion (EMBO Journal 4,3193-3201 (1993) ; also submitted to J.Mol.Biol.)4) Prediction of the three-dimensional structures for various Type I interferons.Structure prediction was done for the following four interferons : human-alphaD,human-beta, bovine & ovine tau's. A huge data set of the structure-activity relationship studiesdirected for Type I interferons were compiled and systematically evaluated based on the established three-dimensional structure(Pharmacology & Therapeutics, 58,93-132 (1993)).5) Yet another challenege for the crystallization of human interferon-alpha.13EA10 : The attempt failed as before indicating that there must be some fundamental reason for non-crystallizability. More systematic approaches making use of a dynamic light scattering device (for example) would be necessary.