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Bridging structural and cell biology with cryo-electron microscopy

Most life scientists would agree that understanding how cellular processes work requires structural knowledge about the macromolecules involved. For example, deciphering the double-helical nature of DNA revealed essential aspects of how genetic information is stored, copied and repaired. Yet, being reductionist in nature, structural biology requires the purification of large amounts of macromolecules, often trimmed off larger functional units. The advent of cryogenic electron microscopy (cryo-EM) greatly facilitated the study of large, functional complexes and generally of samples that are hard to express, purify and/or crystallize. Nevertheless, cryo-EM still requires purification and thus visualization outside of the natural context in which macromolecules operate and coexist. Conversely, cell biologists have been imaging cells using a number of fast-evolving techniques that keep expanding their spatial and temporal reach, but always far from the resolution at which chemistr ....

South Korea , Protein Data Bank , Pdb Consortium , Dn Software , Protein Data , Trends Cell Biol , Cell Biol , Computer Vision , Pattern Recognition , Machine Learning , Life Sci , Acids Res , Electron Microscopy Public Image , Nucleic Acids Res ,

Targeted protein degradation via intramolecular bivalent glues

Targeted protein degradation is a pharmacological modality that is based on the induced proximity of an E3 ubiquitin ligase and a target protein to promote target ubiquitination and proteasomal degradation. This has been achieved either via proteolysis-targeting chimeras (PROTACs)—bifunctional compounds composed of two separate moieties that individually bind the target and E3 ligase, or via molecular glues that monovalently bind either the ligase or the target1–4. Here, using orthogonal genetic screening, biophysical characterization and structural reconstitution, we investigate the mechanism of action of bifunctional degraders of BRD2 and BRD4, termed intramolecular bivalent glues (IBGs), and find that instead of connecting target and ligase in trans as PROTACs do, they simultaneously engage and connect two adjacent domains of the target protein in cis. This conformational change ‘glues’ BRD4 to the E3 ligases DCAF11 or DCAF16, leveraging intrinsic target̵ ....

South Korea , Van Molle , Acta Crystallogr , Development Of Bromotag , Drug Discovery , Nucleic Acids Res , Acids Res , Graphics System ,

Proteins with alpha helices alone and beta sheets alone? - Information

Proteins with alpha helices alone and beta sheets alone? - Information
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South Korea , United States , New York , University Of California At Berkeley , Lawrence Livermore National Laboratory , Andhra Pradesh , Tamil Nadu , United Kingdom , Bobby Schnabel , Robert Corey , Eduardo Roman , Herman Branson , Uniprot Knowledgebase , Gopinath Kartha , Silvia Crivelli , Kalpha Complexed , Deepika Calidas , Alexander Rich , Easwara Subramanian , Lawrence Bragg , Nelson Max , Linus Pauling , Richard Byrd , Oliver Kreylos , Ma Van Leeuwen , Davis Bernd Hamann ,

Functional genomics and systems biology in human neuroscience

Neuroscience research has entered a phase of key discoveries in the realm of neurogenomics owing to strong financial and intellectual support for resource building and tool development. The previous challenge of tissue heterogeneity has been met with the application of techniques that can profile individual cells at scale. Moreover, the ability to perturb genes, gene regulatory elements and neuronal activity in a cell-type-specific manner has been integrated with gene expression studies to uncover the functional underpinnings of the genome at a systems level. Although these insights have necessarily been grounded in model systems, we now have the opportunity to apply these approaches in humans and in human tissue, thanks to advances in human genetics, brain imaging and tissue collection. We acknowledge that there will probably always be limits to the extent to which we can apply the genomic tools developed in model systems to human neuroscience; however, as we describe in this Perspect ....

Le Bihan , Acta Neuropathol , Ng Development , Brain Initiative Cell Census Network , Foundational Data Initiative For Parkinson , N Accelerating Medicines Partnership , Stem Cell , Brain Initiative Cell Census , Tabula Sapiens , Nucleic Acids Res , Proteomics Bioinformatics , Cell Biol , United Kingdom Biobank , United Kingdom , Medicines Partnership , Foundational Data Initiative ,

The status of the human gene catalogue

Scientists have been trying to identify every gene in the human genome since the initial draft was published in 2001. In the years since, much progress has been made in identifying protein-coding genes, currently estimated to number fewer than 20,000, with an ever-expanding number of distinct protein-coding isoforms. Here we review the status of the human gene catalogue and the efforts to complete it in recent years. Beside the ongoing annotation of protein-coding genes, their isoforms and pseudogenes, the invention of high-throughput RNA sequencing and other technological breakthroughs have led to a rapid growth in the number of reported non-coding RNA genes. For most of these non-coding RNAs, the functional relevance is currently unclear; we look at recent advances that offer paths forward to identifying their functions and towards eventually completing the human gene catalogue. Finally, we examine the need for a universal annotation standard that includes all medically significant g ....

Puerto Rico , United States , Puerto Rican , Human Services , Encode Project Consortium , Rnacentral Consortium , Gtex Consortium , Us Department Of Health , Us Department Of Energy , International Human Genome Sequencing Consortium , Uniprot Consortium , Genetic Inheritance , Genome Project , First Five Years , Encode Project , Acids Res , Human Genome Sequencing , Genome Biol , Cell Biol , Ensembl Variant Effect Predictor A , Southern Han Chinese , Nucleic Acids Res ,