title: Proline primed helix length as a modulator of the nuclear receptor-coactivator interaction.
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.
authors: Laboratory of Chemical Biology, Department of Biomedical Engineering, Technische Universiteit Eindhoven, Den Dolech 2, 5612 AZ Eindhoven, The Netherlands.
authors: Sascha
authors: S
authors: Fuchs
authors: Hoang D
authors: HD
authors: Nguyen
authors: Trang T P
authors: TT
authors: Phan
authors: Matthew F
authors: MF
authors: Burton
authors: Lidia
authors: L
authors: Nieto
authors: Ingrid J
authors: IJ
authors: de Vries-van Leeuwen
authors: Andrea
authors: A
authors: Schmidt
authors: Monireh
authors: M
authors: Goodarzifard
authors: Stijn M
authors: SM
authors: Agten
authors: Rolf
authors: R
authors: Rose
authors: Christian
authors: C
authors: Ottmann
authors: Lech-Gustav
authors: LG
authors: Milroy
authors: Luc
authors: L
authors: Brunsveld
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D016384:Consensus Sequence; D018360:Crystallography, X-Ray; D015723:Gene Library; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011392:Proline / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011960:Receptors, Estrogen / Q000737:chemistry / Q000378:metabolism*
chemical_list: D019151:Peptide Library; D010455:Peptides; D011960:Receptors, Estrogen; D011392:Proline