Proline Primed Helix Length as a Modulator of the Nuclear Receptor–Coactivator Interaction

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 under...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2013-03, Vol.135 (11), p.4364-4371
Main Authors: Fuchs, Sascha, Nguyen, Hoang D, Phan, Trang T. P, Burton, Matthew F, Nieto, Lidia, de Vries-van Leeuwen, Ingrid J, Schmidt, Andrea, Goodarzifard, Monireh, Agten, Stijn M, Rose, Rolf, Ottmann, Christian, Milroy, Lech-Gustav, Brunsveld, Luc
Format: Article
Language:English
Subjects:
Amino Acid Motifs
Amino Acid Sequence
Consensus Sequence
Crystallography, X-Ray
Gene Library
Humans
Models, Molecular
Molecular Sequence Data
Peptide Library
Peptides - chemistry
Peptides - metabolism
Proline - chemistry
Proline - metabolism
Protein Binding
Protein Structure, Secondary
Receptors, Estrogen - chemistry
Receptors, Estrogen - metabolism
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Summary: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.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja311748r