Image-based profiling is a maturing strategy by which the rich information present in biological images is reduced to a multidimensional profile, a collection of extracted image-based features. These profiles can be mined for relevant patterns, revealing unexpected biological activity that is useful for many steps in the drug discovery process. Such applications include identifying disease-associated screenable phenotypes, understanding disease mechanisms and predicting a drug’s activity, toxicity or mechanism of action. Several of these applications have been recently validated and have moved into production mode within academia and the pharmaceutical industry. Some of these have yielded disappointing results in practice but are now of renewed interest due to improved machine-learning strategies that better leverage image-based information. Although challenges remain, novel computational technologies such as deep learning and single-cell methods that better capture the biological information in images hold promise for accelerating drug discovery. Image-based profiling is a strategy to mine the rich information in biological images. Carpenter and colleagues discuss how the application of machine learning is renewing interest in image-based profiling for all aspects of the drug discovery process, from understanding disease mechanisms to predicting a drug’s activity or mechanism of action.

/pdf/image-based-profiling-for-drug-discovery-due-for-a-machine-hofne3v8lb.pdf

Image-based profiling for drug discovery: due for a machine-learning upgrade?

Morphological profiling of small molecules.

Structure and reconstitution of yeast Mpp6-nuclear exosome complexes reveals that Mpp6 stimulates RNA decay and recruits the Mtr4 helicase

The conserved 3'-5' exoribonuclease EXOSC10/Rrp6 processes and degrades RNA, regulates gene expression and participates in DNA double-strand break repair and control of telomere maintenance via degradation of the telomerase RNA component. EXOSC10/Rrp6 is part of the multimeric nuclear RNA exosome and interacts with numerous proteins. Previous clinical, genetic, biochemical and genomic studies revealed the protein's essential functions in cell division and differentiation, its RNA substrates and its relevance to autoimmune disorders and oncology. However, little is known about the regulatory mechanisms that control the transcription, translation and stability of EXOSC10/Rrp6 during cell growth, development and disease and how these mechanisms evolved from yeast to human. Herein, we provide an overview of the RNA- and protein expression profiles of EXOSC10/Rrp6 during cell division, development and nutritional stress, and we summarize interaction networks and post-translational modifications across species. Additionally, we discuss how known and predicted protein interactions and post-translational modifications influence the stability of EXOSC10/Rrp6. Finally, we explore the idea that different EXOSC10/Rrp6 alleles, which potentially alter cellular protein levels or affect protein function, might influence human development and disease progression. In this review we interpret information from the literature together with genomic data from knowledgebases to inspire future work on the regulation of this essential protein's stability in normal and malignant cells.

/pdf/regulation-of-the-conserved-3-5-exoribonuclease-exosc10-rrp6-4riembkqlb.pdf

Regulation of the conserved 3'-5' exoribonuclease EXOSC10/Rrp6 during cell division, development and cancer.

The exoribonuclease Rrp6p is critical for RNA decay in the nucleus. While Rrp6p acts on a large range of diverse substrates, it does not indiscriminately degrade all RNAs. How Rrp6p accomplishes this task is not understood. Here, we measure Rrp6p-RNA binding and degradation kinetics in vitro at single-nucleotide resolution and find an intrinsic substrate selectivity that enables Rrp6p to discriminate against specific RNAs. RNA length and the four 3'-terminal nucleotides contribute most to substrate selectivity and collectively enable Rrp6p to discriminate between different RNAs by several orders of magnitude. The most pronounced discrimination is seen against RNAs ending with CCA-3'. These RNAs correspond to 3' termini of uncharged tRNAs, which are not targeted by Rrp6p in cells. The data show that in contrast to many other proteins that use substrate selectivity to preferentially interact with specific RNAs, Rrp6p utilizes its selectivity to discriminate against specific RNAs. This ability allows Rrp6p to target diverse substrates while avoiding a subset of RNAs.

Substrate selectivity by the exonuclease Rrp6p.

Structure and Function of the Bacterial Protein Toxin Phenomycin.

Phenomycin is a bacterial mini-protein of 89 amino acids discovered more than 50 years ago with toxicity in the nanomolar regime towards mammalian cells. The protein inhibits the function of the eukaryotic ribosome in cell free systems and appears to target translation initiation. Several fundamental questions concerning the cellular activity of phenomycin have however remained unanswered. In this paper, we have used morphological profiling to show that direct inhibition of translation underlies the toxicity of phenomycin in cells. We have performed studies of the cellular uptake mechanism of phenomycin, showing that endosomal escape is the toxicity-limiting step, and we have solved a solution phase high-resolution structure of the protein using NMR spectroscopy. Through bioinformatic as well as functional comparisons between phenomycin and two homologs, we have identified a peptide segment which constitutes one of two loops in the structure that is critical for the toxicity of phenomycin.

https://www.biorxiv.org/content/biorxiv/early/2019/11/29/847772.full.pdf

Structure and function of the bacterial protein toxin phenomycin

During neuronal development axons are guided by a gradient of the signal molecule netrin, which attracts extending neurons by binding to the DCC (Deleted in Colorectal Cancer) Receptor. It has been shown that the intracellular domain of the DCC receptor interacts directly with the ribosome, and that this interaction is crucial for axon guidance(1). However structural insights into this interaction are still lacking. Our aim is therefore to determine the crystal structure of the DCC-ribosome complex. As membrane proteins can be challenging to crystalize, especially together with a huge macromolecular complex as the ribosome, a cloned fragment of the intracellular domain of the human DCC receptor will be used. Tcherkezian et al. showed that the interaction with the ribosome occurs through the ribosomal protein L5(1), which is conserved from S. cerevisiae to humans. We therefore decided to use the 80S S. cerevisiae ribosome because crystallization conditions are known and well-established (2). Furthermore, in the crystals of S. cerevisiae there is a large solvent channel passing by ribosomal protein L5(2), making it likely that we can soak fragments of the DCC receptor into crystals of S. cerevisiae ribosome. In order to screen for soluble fragments of the DCC receptor that can be used for soaking, a random PCR expression approach first described by Kawasaki and Inagaki(3), where random PCR fragments are inserted into a vector containing GFP was used. This method resulted in several soluble fragments covering the P1 domain that was shown to be responsible for ribosome binding(1). These fragments are now being purified, and will be tested for ribosome binding, and subsequently in soaking and co-crystallisation experiments. Progress will be presented.

/pdf/structural-studies-of-the-dcc-ribosome-complex-4zjvzct9p1.pdf

Structural Studies of the DCC-Ribosome Complex

http://pure.au.dk/portal/files/81418286/Dedic_et_al._2014.pdf

Structural analysis of the yeast exosome Rrp6p–Rrp47p complex by small-angle X-ray scattering

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Papers

Structure and Function of the Bacterial Protein Toxin Phenomycin.

Structure and function of the bacterial protein toxin phenomycin

Structural Studies of the DCC-Ribosome Complex

Structural analysis of the yeast exosome Rrp6p–Rrp47p complex by small-angle X-ray scattering