Dataset Information

Targeting Protein-Protein Interactions in the HIF System.

ABSTRACT: Animals respond to chronic hypoxia by increasing the levels of a transcription factor known as the hypoxia-inducible factor (HIF). HIF upregulates multiple genes, the products of which work to ameliorate the effects of limited oxygen at cellular and systemic levels. Hypoxia sensing by the HIF system involves hydroxylase-catalysed post-translational modifications of the HIF ?-subunits, which 1)?signal for degradation of HIF-? and 2)?limit binding of HIF to transcriptional coactivator proteins. Because the hypoxic response is relevant to multiple disease states, therapeutic manipulation of the HIF-mediated response has considerable medicinal potential. In addition to modulation of catalysis by the HIF hydroxylases, the HIF system manifests other possibilities for therapeutic intervention involving protein-protein and protein-nucleic acid interactions. Recent advances in our understanding of the structural biology and biochemistry of the HIF system are facilitating medicinal chemistry efforts. Herein we give an overview of the HIF system, focusing on structural knowledge of protein-protein interactions and how this might be used to modulate the hypoxic response for therapeutic benefit.

SUBMITTER: Wilkins SE

PROVIDER: S-EPMC4848768 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Targeting Protein-Protein Interactions in the HIF System.

Wilkins Sarah E SE Abboud Martine I MI Hancock Rebecca L RL Schofield Christopher J CJ

ChemMedChem 20160321 8

Animals respond to chronic hypoxia by increasing the levels of a transcription factor known as the hypoxia-inducible factor (HIF). HIF upregulates multiple genes, the products of which work to ameliorate the effects of limited oxygen at cellular and systemic levels. Hypoxia sensing by the HIF system involves hydroxylase-catalysed post-translational modifications of the HIF α-subunits, which 1) signal for degradation of HIF-α and 2) limit binding of HIF to transcriptional coactivator proteins. Be ...[more]

PMID: 26997519

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Project description:Finding new drug targets for pathogenic infections would be of great utility for humanity, as there is a large need to develop new drugs to fight infections due to the developing resistance and side effects of current treatments. Current drug targets for pathogen infections involve only a single protein. However, proteins rarely act in isolation, and the majority of biological processes occur via interactions with other proteins, so protein-protein interactions (PPIs) offer a realm of unexplored potential drug targets and are thought to be the next-generation of drug targets. Parasitic worms were chosen for this study because they have deleterious effects on human health, livestock, and plants, costing society billions of dollars annually and many sequenced genomes are available. In this study, we present a computational approach that utilizes whole genomes of 6 parasitic and 1 free-living worm species and 2 hosts. The species were placed in orthologous groups, then binned in species-specific orthologous groups. Proteins that are essential and conserved among species that span a phyla are of greatest value, as they provide foundations for developing broad-control strategies. Two PPI databases were used to find PPIs within the species specific bins. PPIs with unique helminth proteins and helminth proteins with unique features relative to the host, such as indels, were prioritized as drug targets. The PPIs were scored based on RNAi phenotype and homology to the PDB (Protein DataBank). EST data for the various life stages, GO annotation, and druggability were also taken into consideration. Several PPIs emerged from this study as potential drug targets. A few interactions were supported by co-localization of expression in M. incognita (plant parasite) and B. malayi (H. sapiens parasite), which have extremely different modes of parasitism. As more genomes of pathogens are sequenced and PPI databases expanded, this methodology will become increasingly applicable.

Dataset Information

Targeting Protein-Protein Interactions in the HIF System.

Publications

Targeting Protein-Protein Interactions in the HIF System.

Similar Datasets

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