title: Ordering a dynamic protein via a small-molecule stabilizer.
abstract: 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 Å 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.
authors: Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan 48109, United States.
authors: Ningkun
authors: N
authors: Wang
authors: Chinmay Y
authors: CY
authors: Majmudar
authors: William C
authors: WC
authors: Pomerantz
authors: Jessica K
authors: JK
authors: Gagnon
authors: Jack D
authors: JD
authors: Sadowsky
authors: Jennifer L
authors: JL
authors: Meagher
authors: Taylor K
authors: TK
authors: Johnson
authors: Jeanne A
authors: JA
authors: Stuckey
authors: Charles L
authors: CL
authors: Brooks
authors: James A
authors: JA
authors: Wells
authors: Anna K
authors: AK
authors: Mapp
mesh_terms: D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011506:Proteins / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000737:chemistry*; D013499:Surface Properties
chemical_list: D011506:Proteins; D054852:Small Molecule Libraries
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