Browse
Submit Data
Databases
API
Help

Dataset Information

14 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mini review: protein-protein interactions in transcription: a fertile ground for helix mimetics.

ABSTRACT: Designed ligands that inhibit protein-protein interactions involved in gene expression are valuable as reagents for genomics research and as leads for drug discovery efforts. Selective modulation of protein-protein interactions has proven to be a daunting task for synthetic ligands; however, the last decade has seen significant advances in inhibitor design, especially for helical protein interfaces. This review discusses examples of transcriptional complexes targeted by designer helices.

SUBMITTER: Guarracino DA

PROVIDER: S-EPMC2966508 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Mini review: protein-protein interactions in transcription: a fertile ground for helix mimetics.

Guarracino Danielle A DA Bullock Brooke N BN Arora Paramjit S PS

Biopolymers 20110101 1

Designed ligands that inhibit protein-protein interactions involved in gene expression are valuable as reagents for genomics research and as leads for drug discovery efforts. Selective modulation of protein-protein interactions has proven to be a daunting task for synthetic ligands; however, the last decade has seen significant advances in inhibitor design, especially for helical protein interfaces. This review discusses examples of transcriptional complexes targeted by designer helices. ...[more]

PMID: 20882600

Similar Datasets

Novel pyrrolopyrimidine-based ?-helix mimetics: cell-permeable inhibitors of protein?protein interactions.

Project description:There is considerable interest in developing non-peptidic, small-molecule ?-helix mimetics to disrupt ?-helix-mediated protein?protein interactions. Herein, we report the design of a novel pyrrolopyrimidine-based scaffold for such ?-helix mimetics with increased conformational rigidity. We also developed a facile solid-phase synthetic route that is amenable to divergent synthesis of a large library. Using a fluorescence polarization-based assay, we identified cell-permeable, dual MDMX/MDM2 inhibitors, demonstrating that the designed molecules can act as ?-helix mimetics.

| S-EPMC3079198 | biostudies-literature

Probing Protein Surfaces: QSAR Analysis with Helix Mimetics.

Project description:?-Helix-mediated protein-protein interactions (PPIs) are important targets for small-molecule inhibition; however, generic approaches to inhibitor design are in their infancy and would benefit from QSAR analyses to rationalise the noncovalent basis of molecular recognition by designed ligands. Using a helix mimetic based on an oligoamide scaffold, we have exploited the power of a modular synthesis to access compounds that can readily be used to understand the noncovalent determinants of hDM2 recognition by this series of cell-active p53/hDM2 inhibitors.

| S-EPMC6591138 | biostudies-literature

Orthogonal functionalisation of ?-helix mimetics.

Project description:?-Helix mediated protein-protein interactions are of major therapeutic importance. As such, the design of inhibitors of this class of interaction is of significant interest. We present methodology to modify N-alkylated aromatic oligoamide ?-helix mimetics using 'click' chemistry. The effect is shown to modulate the binding properties of a series of selective p53/hDM2 inhibitors.

| S-EPMC4157654 | biostudies-literature

Interactions between basic helix-loop-helix transcription factors and nucleosomes

Project description:In solution crosslinking mass spectrometry of transcription factors in complex with nucleosomes

2023-05-23 | PXD033181 | Pride

The future of male contraception: a fertile ground.

Project description:The continued and rapid expansion of the Earth's population mandates the need for safe and effective measures of contraception. While a plethora of options exist for women, methods of contraception for the male partner are limited to condoms and vasectomy. The sequela of this discrepancy has led to the family planning burden falling disproportionately on the female partner. For the past several decades, extensive research has been undertaken exploring the feasibility of hormonal male contraception. This proposed method of contraception has focused on suppressing spermatogenesis by exploiting the hypothalamic-pituitary-gonadal (HPG) axis. Beginning with proof of concept studies in the early nineties, administration of testosterone in healthy male subjects has been shown to be an efficacious method of inducing sterility. Owing to ethnic differences in spermatogenesis suppression and the comparatively low rate of azoospermia in Caucasian men with androgen-only regimens, investigators have explored the addition of progestins to further enhance the efficacy of hormonal contraception. Though studies have revealed promise with androgen-progestin regimens, the lack of long-term studies has precluded the development of a marketable product. Recently, more research has been directed towards identifying non-hormonal alternatives to male contraception. These non-hormonal options have ranged from the development of devices facilitating reversible occlusion of the vas deferens lumen to medications disrupting various pathways in the process of spermatogenesis. Underlying the development of hormonal and non-hormonal strategies is the shared enthusiasm men and women have towards these male directed methods. The willingness of couples to pursue these alternatives combined with the global need to reduce the psychological and socioeconomic implications of unintended pregnancy ensures that research will continue to bring this goal to fruition.

| S-EPMC5989114 | biostudies-literature

Homodimeric and Heterodimeric Interactions among Vertebrate Basic Helix-Loop-Helix Transcription Factors.

Project description:The basic helix-loop-helix transcription factor (bHLH TF) family is involved in tissue development, cell differentiation, and disease. These factors have transcriptionally positive, negative, and inactive functions by combining dimeric interactions among family members. The best known bHLH TFs are the E-protein homodimers and heterodimers with the tissue-specific TFs or ID proteins. These cooperative and dynamic interactions result in a complex transcriptional network that helps define the cell's fate. Here, the reported dimeric interactions of 67 vertebrate bHLH TFs with other family members are summarized in tables, including specifications of the experimental techniques that defined the dimers. The compilation of these extensive data underscores homodimers of tissue-specific bHLH TFs as a central part of the bHLH regulatory network, with relevant positive and negative transcriptional regulatory roles. Furthermore, some sequence-specific TFs can also form transcriptionally inactive heterodimers with each other. The function, classification, and developmental role for all vertebrate bHLH TFs in four major classes are detailed.

| S-EPMC8657788 | biostudies-literature

Perturbation of the c-Myc-Max protein-protein interaction via synthetic α-helix mimetics.

Project description:The rational design of inhibitors of the bHLH-ZIP oncoprotein c-Myc is hampered by a lack of structure in its monomeric state. We describe herein the design of novel, low-molecular-weight, synthetic α-helix mimetics that recognize helical c-Myc in its transcriptionally active coiled-coil structure in association with its obligate bHLH-ZIP partner Max. These compounds perturb the heterodimer's binding to its canonical E-box DNA sequence without causing protein-protein dissociation, heralding a new mechanistic class of "direct" c-Myc inhibitors. In addition to electrophoretic mobility shift assays, this model was corroborated by further biophysical methods, including NMR spectroscopy and surface plasmon resonance. Several compounds demonstrated a 2-fold or greater selectivity for c-Myc-Max heterodimers over Max-Max homodimers with IC50 values as low as 5.6 μM. Finally, these compounds inhibited the proliferation of c-Myc-expressing cell lines in a concentration-dependent manner that correlated with the loss of expression of a c-Myc-dependent reporter plasmid despite the fact that c-Myc-Max heterodimers remained intact.

| S-EPMC4955407 | biostudies-literature

Functional probes of drug-receptor interactions implicated by structural studies: Cys-loop receptors provide a fertile testing ground.

Project description:Structures of integral membrane receptors provide valuable models for drug-receptor interactions across many important classes of drug targets and have become much more widely available in recent years. However, it remains to be determined to what extent these images are relevant to human receptors in their biological context and how subtle issues such as subtype selectivity can be informed by them. The high precision structural modifications enabled by unnatural amino acid mutagenesis on mammalian receptors expressed in vertebrate cells allow detailed tests of predictions from structural studies. Using the Cys-loop superfamily of ligand-gated ion channels, we show that functional studies lead to detailed binding models that, at times, are significantly at odds with the structural studies on related invertebrate proteins. Importantly, broad variations in binding interactions are seen for very closely related receptor subtypes and for varying drugs at a given binding site. These studies highlight the essential interplay between structural studies and functional studies that can guide efforts to develop new pharmaceuticals.

| S-EPMC4136689 | biostudies-literature

Aromatic Foldamer Helices as ?-Helix Extended Surface Mimetics.

Project description:Helically folded aromatic oligoamide foldamers have a size and geometrical parameters very distinct from those of ?-helices and are not obvious candidates for ?-helix mimicry. Nevertheless, they offer multiple sites for attaching side chains. It was found that some arrays of side chains at the surface of an aromatic helix make it possible to mimic extended ?-helical surfaces. Synthetic methods were developed to produce quinoline monomers suitably functionalized for solid phase synthesis. A dodecamer was prepared. Its crystal structure validated the initial design and showed helix bundling involving the ?-helix-like interface. These results open up new uses of aromatic helices to recognize protein surfaces and to program helix bundling in water.

| S-EPMC7839445 | biostudies-literature

Balancing Force Field Protein-Lipid Interactions To Capture Transmembrane Helix-Helix Association.

Project description:Atomistic simulations have recently been shown to be sufficiently accurate to reversibly fold globular proteins and have provided insights into folding mechanisms. Gaining similar understanding from simulations of membrane protein folding and association would be of great medical interest. All-atom simulations of the folding and assembly of transmembrane protein domains are much more challenging, not least due to very slow diffusion within the lipid bilayer membrane. Here, we focus on a simple and well-characterized prototype of membrane protein folding and assembly, namely the dimerization of glycophorin A, a homodimer of single transmembrane helices. We have determined the free energy landscape for association of the dimer using the CHARMM36 force field. We find that the native structure is a metastable state, but not stable as expected from experimental estimates of the dissociation constant and numerous experimental structures obtained under a variety of conditions. We explore two straightforward approaches to address this problem and demonstrate that they result in stable dimers with dissociation constants consistent with experimental data.

| S-EPMC5852462 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data