Ordering a dynamic protein Via a small-molecule stabilizer

Ningkun Wang, Chinmay Y. Majmudar, William C. Pomerantz, Jessica K. Gagnon, Jack D. Sadowsky, Jennifer L. Meagher, Taylor K. Johnson, Jeanne A. Stuckey, Charles L. Brooks, James A. Wells, Anna K. Mapp

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3363-3366
Number of pages4
JournalJournal of the American Chemical Society
Volume135
Issue number9
DOIs
StatePublished - Mar 6 2013

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p300-CBP Transcription Factors
Molecular Dynamics Simulation
Binding Sites
Ligands
Proteins
Molecules
Binding sites
Modulators
Molecular dynamics
Computer simulation
Chemical analysis

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Wang, N., Majmudar, C. Y., Pomerantz, W. C., Gagnon, J. K., Sadowsky, J. D., Meagher, J. L., ... Mapp, A. K. (2013). Ordering a dynamic protein Via a small-molecule stabilizer. Journal of the American Chemical Society, 135(9), 3363-3366. https://doi.org/10.1021/ja3122334

Ordering a dynamic protein Via a small-molecule stabilizer. / Wang, Ningkun; Majmudar, Chinmay Y.; Pomerantz, William C.; Gagnon, Jessica K.; Sadowsky, Jack D.; Meagher, Jennifer L.; Johnson, Taylor K.; Stuckey, Jeanne A.; Brooks, Charles L.; Wells, James A.; Mapp, Anna K.

In: Journal of the American Chemical Society, Vol. 135, No. 9, 06.03.2013, p. 3363-3366.

Research output: Contribution to journalArticle

Wang, N, Majmudar, CY, Pomerantz, WC, Gagnon, JK, Sadowsky, JD, Meagher, JL, Johnson, TK, Stuckey, JA, Brooks, CL, Wells, JA & Mapp, AK 2013, 'Ordering a dynamic protein Via a small-molecule stabilizer', Journal of the American Chemical Society, vol. 135, no. 9, pp. 3363-3366. https://doi.org/10.1021/ja3122334
Wang, Ningkun ; Majmudar, Chinmay Y. ; Pomerantz, William C. ; Gagnon, Jessica K. ; Sadowsky, Jack D. ; Meagher, Jennifer L. ; Johnson, Taylor K. ; Stuckey, Jeanne A. ; Brooks, Charles L. ; Wells, James A. ; Mapp, Anna K. / Ordering a dynamic protein Via a small-molecule stabilizer. In: Journal of the American Chemical Society. 2013 ; Vol. 135, No. 9. pp. 3363-3366.
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