Journal ArticleDOI
Design and structure of stapled peptides binding to estrogen receptors.
Chris Phillips,Lee R. Roberts,Markus Schade,Richard Bazin,Andrew F. Bent,Nichola L. Davies,Robert Moore,Andrew Pannifer,Andrew R. Pickford,Stephen H. Prior,Christopher M. Read,Andrew D. Scott,David G. Brown,Bin Xu,Stephen L. Irving +14 more
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TLDR
This work describes the design of a series of novel stapled peptides that bind the coactivator peptide site of estrogen receptors and demonstrates that all-hydrocarbon staples modulate molecular recognition events.Abstract:
Synthetic peptides that specifically bind nuclear hormone receptors offer an alternative approach to small molecules for the modulation of receptor signaling and subsequent gene expression. Here we describe the design of a series of novel stapled peptides that bind the coactivator peptide site of estrogen receptors. Using a number of biophysical techniques, including crystal structure analysis of receptor–stapled peptide complexes, we describe in detail the molecular interactions and demonstrate that all-hydrocarbon staples modulate molecular recognition events. The findings have implications for the design of stapled peptides in general.read more
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Coronavirus envelope protein: current knowledge
TL;DR: Data shows that E is involved in critical aspects of the viral life cycle and that CoVs lacking E make promising vaccine candidates, which can aid in the production of effective anti-coronaviral agents for both human CoVs and enzootic CoVs.
Journal ArticleDOI
Inhibition of α-helix-mediated protein–protein interactions using designed molecules
TL;DR: This Review discusses the relevance of PPIs and, in particular, the importance of α-helix-mediated PPIs to chemical biology and drug discovery with a focus on designing inhibitors, including constrained peptides, foldamers and proteomimetic-derived ligands.
Journal ArticleDOI
Stapled α−helical peptide drug development: A potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy
Yong S. Chang,Bradford Graves,Vincent Guerlavais,Christian Tovar,Packman Kathryn E,Kwong-Him To,Karen A. Olson,Kamala Kesavan,Pranoti Gangurde,Aditi Mukherjee,Theresa Baker,Krzysztof Darlak,Carl Elkin,Zoran Filipovic,Farooq Qureshi,Hongliang Cai,Pamela Berry,Eric Feyfant,Xiangguo E. Shi,James Horstick,D. Allen Annis,Anthony M. Manning,Nader Fotouhi,Huw M. Nash,Lyubomir T. Vassilev,Tomi K. Sawyer +25 more
TL;DR: Overall, ATSP-7041 demonstrates in vitro and in vivo proof-of-concept that stapled peptides can be developed as therapeutically relevant inhibitors of protein–protein interaction and may offer a viable modality for cancer therapy.
Journal ArticleDOI
Structure-Based Design of Inhibitors of Protein-Protein Interactions: Mimicking Peptide Binding Epitopes
TL;DR: A new classification of peptidomimetics (classes A–D) is introduced that enables a clear assignment of available approaches for the structure-based design of PPI inhibitors through stabilizing or mimicking turns, β-sheets, and helices.
Journal ArticleDOI
Modulators of Protein-Protein Interactions
TL;DR: This research presents a novel and scalable approaches called “Smart Gene Regulation” that allows for real-time annotation of the FISH signal in the Eindhoven–Borff–Seiden cellular automaton.
References
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Journal ArticleDOI
Molecular basis of agonism and antagonism in the oestrogen receptor.
Andrzej M. Brzozowski,Ashley C. W. Pike,Zbigniew Dauter,Roderick E. Hubbard,Tomas Bonn,Owe Engström,Lars Öhman,Geoffrey L. Greene,Jan-Åke Gustafsson,Mats Carlquist +9 more
TL;DR: The crystal structures of the LBD of ER in complex with the endogenous oestrogen, 17β-oestradiol, and the selective antagonist raloxifene provide a molecular basis for the distinctive pharmacophore of the ER and its catholic binding properties.
Journal ArticleDOI
The druggable genome
Andrew L. Hopkins,Colin R. Groom +1 more
TL;DR: An assessment of the number of molecular targets that represent an opportunity for therapeutic intervention is crucial to the development of post-genomic research strategies within the pharmaceutical industry.
Journal ArticleDOI
The Structural Basis of Estrogen Receptor/Coactivator Recognition and the Antagonism of This Interaction by Tamoxifen
Andrew K. Shiau,Danielle Barstad,Paula M. Loria,Lin Cheng,Peter J. Kushner,David A. Agard,Geoffrey L. Greene +6 more
TL;DR: Crystal structures of the human estrogen receptor alpha (hER alpha) ligand-binding domain (LBD) and the OHT-LBD complex reveal the two distinct mechanisms by which structural features of OHT promote this "autoinhibitory" helix 12 conformation.
Journal ArticleDOI
A signature motif in transcriptional co-activators mediates binding to nuclear receptors.
TL;DR: It is proposed that the LXXLL motif is a signature sequence that facilitates the interaction of different proteins with nuclear receptors, and is thus a defining feature of a new family of nuclear proteins.
Journal ArticleDOI
Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma.
Robert T. Nolte,G. B. Wisely,Stefan Westin,Cobb Jeffrey Edmond,Millard H. Lambert,Riki Kurokawa,Michael G. Rosenfeld,Timothy M. Willson,Christopher K. Glass,Michael V. Milburn +9 more
TL;DR: A general mechanism for the assembly of nuclear receptors with co-activators is suggested, based on the observation that two consecutive LXXLL motifs of SRC-1 make identical contacts with both subunits of a PPAR-γ homodimer.
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Stapled α−helical peptide drug development: A potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy
Yong S. Chang,Bradford Graves,Vincent Guerlavais,Christian Tovar,Packman Kathryn E,Kwong-Him To,Karen A. Olson,Kamala Kesavan,Pranoti Gangurde,Aditi Mukherjee,Theresa Baker,Krzysztof Darlak,Carl Elkin,Zoran Filipovic,Farooq Qureshi,Hongliang Cai,Pamela Berry,Eric Feyfant,Xiangguo E. Shi,James Horstick,D. Allen Annis,Anthony M. Manning,Nader Fotouhi,Huw M. Nash,Lyubomir T. Vassilev,Tomi K. Sawyer +25 more