Like many coactivators, the GACKIX domain of the master coactivator CBP/p300 recognizes transcriptional activators of diverse sequence composition via dynamic binding surfaces. The conformational dynamics of GACKIX that underlie its function also render it especially challenging for structural characterization. We have found that the ligand discovery strategy of Tethering is an effective method for identifying small-molecule fragments that stabilize the GACKIX domain, enabling for the first time the crystallographic characterization of this important motif. The 2.0 angstrom resolution structure of GACKIX complexed to a small molecule was further analyzed by molecular dynamics simulations, which revealed the importance of specific side-chain motions that remodel the activator binding site in order to accommodate binding partners of distinct sequence and size. More broadly, these results suggest that Tethering can be a powerful strategy for identifying small-molecule stabilizers of conformationally malleable proteins, thus facilitating their structural characterization and accelerating the discovery of small-molecule modulators.