Proline primed helix length as a modulator of the nuclear receptor-coactivator interaction
| Autor: | Sascha Fuchs, Matthew F. Burton, Christian Ottmann, Lidia Nieto, Stijn M. Agten, Andrea Schmidt, Trang Thi Phuong Phan, Luc Brunsveld, Ingrid J. de Vries-van Leeuwen, Monireh Goodarzifard, Lech-Gustav Milroy, Hoang Duc Nguyen, Rolf Rose |
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| Přispěvatelé: | Chemical Biology |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Proline Molecular model Amino Acid Motifs Molecular Sequence Data Estrogen receptor Priming (immunology) Peptide Crystallography X-Ray Biochemistry Protein Structure Secondary Catalysis Colloid and Surface Chemistry Peptide Library Consensus Sequence Coactivator Humans Amino Acid Sequence Gene Library chemistry.chemical_classification Chemistry General Chemistry Amino acid Cell biology Receptors Estrogen Nuclear receptor Ribosome display Peptides Protein Binding |
| Zdroj: | Journal of the American Chemical Society, 135(11), 4364-4371. American Chemical Society |
| ISSN: | 1520-5126 0002-7863 |
| Popis: | 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-protein 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 α-helix and enabling optimal interactions of the α-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-coactivator interaction based on linear sequences of proteinogenic amino acids and for the design of chemically modified inhibitors. |
| Databáze: | OpenAIRE |
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