4J26

Estrogen Receptor in complex with proline-flanked LXXLL peptides

Summary for 4J26

• Entry DOI: 10.2210/pdb4j26/pdb
• Related: 3OLL 4J24
• Descriptor: Estrogen receptor beta, 12-mer Peptide, ESTRADIOL, ... (4 entities in total)
• Functional Keywords: estrogen receptor, proline, lxxll, alpha-helix, structure stabilization, hormone receptor-peptide complex, hormone receptor/peptide
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q92731
• Total number of polymer chains: 4
• Total formula weight: 57672.62

Authors

Fuchs, S.,Nguyen, H.D.,Phan, T.,Burton, M.,Nieto, L.,de Vries-van Leeuwen, I.,Schmidt, A.,Goodarzifard, M.,Agten, S.,Rose, R.,Ottmann, C.,Milroy, L.G.,Brunsveld, L. (deposition date: 2013-02-04, release date: 2013-03-13, Last modification date: 2023-11-08)

Primary citation

Fuchs, S.,Nguyen, H.D.,Phan, T.T.,Burton, M.F.,Nieto, L.,de Vries-van Leeuwen, I.J.,Schmidt, A.,Goodarzifard, M.,Agten, S.M.,Rose, R.,Ottmann, C.,Milroy, L.G.,Brunsveld, L.
Proline primed helix length as a modulator of the nuclear receptor-coactivator interaction
J.Am.Chem.Soc., 135:4364-4371, 2013

PubMed Abstract: 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.

PubMed: 23437920
DOI: 10.1021/ja311748r

Experimental method

X-RAY DIFFRACTION (2.3 Å)