Compositions and methods for inducing conformational changes in cereblon and other E3 ubiquitin ligases

A method of identifying a test compound that induces a cereblon protein (CRBN) conformational change or an alteration of properties of a CRBN surface, wherein the method comprises:

• (a) (i) obtaining a first crystal of CRBN and a reference compound or an apo-CRBN crystal, and (ii) determining the three-dimensional structure of the first crystal by x-ray diffraction to obtain a first set of atomic coordinates;
• (b) (i) obtaining a second crystal comprising CRBN and the test compound, and (ii) determining the three-dimensional structure of the second crystal by x-ray diffraction to obtain a second set of atomic coordinates;
• and
• (c) employing on a computer, the structural coordinates from the first set of atomic coordinates and the second set of atomic coordinates and comparing the two sets with one another wherein identification of a test compound that induces a conformational change or alteration of properties of a CRBN surface is made by identifying a shift in the protein backbone or sidechains in the second set of atomic coordinates as compared to the first set atomic coordinates;
• wherein the CRBN conformational change or the alteration of properties of the CRBN surface occurs in a CRBN modifying agent (CMA) binding pocket of the CRBN, or within an adjacent region thereof, and
• wherein said first and second crystals comprising CRBN form in space group P212121 or /23 and are human or murine CRBN.