Proline Primed Helix Length as a Modulator of the Nuclear Receptor鈥揅oactivator Interaction

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• 作者：Sascha Fuchs ; Hoang D. Nguyen ; Trang T. P. Phan ; Matthew F. Burton ; Lidia Nieto ; Ingrid J. de Vries-van Leeuwen ; Andrea Schmidt ; Monireh Goodarzifard ; Stijn M. Agten ; Rolf Rose ; Christian Ottmann ; Lech-Gustav Milroy ; Luc Brunsveld
• 刊名：The Journal of the American Chemical Society
• 出版年：2013
• 出版时间：March 20, 2013
• 年：2013
• 卷：135
• 期：11
• 页码：4364-4371
• 全文大小：518K
• 年卷期：v.135,no.11(March 20, 2013)
• ISSN：1520-5126

文摘

Nuclear receptor binding to coactivator proteins is an obligate first step in the regulation of gene transcription. Nuclear receptors preferentially bind to an LXXLL peptide motif which is highly conserved throughout the 300 or so natural coactivator proteins. This knowledge has shaped current understanding of this fundamental protein鈥損rotein interaction, and continues to inspire the search for new drug therapies. However, sequence specificity beyond the LXXLL motif and the molecular functioning of flanking residues still requires urgent addressing. Here, ribosome display has been used to reassess the estrogen receptor for new and enlarged peptide recognition motifs, leading to the discovery of a potent and highly evolved PXLXXLLXXP binding consensus. Molecular modeling and X-ray crystallography studies have provided the molecular insights on the role of the flanking prolines in priming the length of the 伪-helix and enabling optimal interactions of the 伪-helix dipole and its surrounding amino acids with the surface charge clamp and the receptor activation function 2. These findings represent new structural parameters for modulating the nuclear receptor鈥揷oactivator interaction based on linear sequences of proteinogenic amino acids and for the design of chemically modified inhibitors.