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471 results for “Protein targets”
Dataset / Code: Targeted protein degradation in mycobacteria uncovers antibacterial effects and potentiates antibiotic efficacy
<p><strong>Targeted protein degradation in mycobacteria uncovers antibacterial effects and potentiates antibiotic efficacy</strong></p> <p><strong> </strong></p> <p>Harim I. Won<sup>1,#</sup>, Samuel Zinga<sup>1,#</sup>, Olga Kandror<sup>1</sup>, Tatos Akopian<sup>1</sup>, Ian D. Wolf<sup>1</sup>, Jessica T.P. Schweber<sup>1</sup>, Ernst W. Schmid<sup>2</sup>, Michael C. Chao<sup>1</sup>, Maya Waldor<sup>1</sup>, Eric J. Rubin<sup>1,*</sup>, Junhao Zhu<sup>1,3,*</sup></p> <p><strong> </strong></p> <p><sup>1</sup>Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.</p> <p><sup>2</sup>Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Blavatnik Institute, Boston, Massachusetts 02115, USA.</p> <p><sup>3</sup>CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.</p> <p><sup>#</sup>These authors contributed equally to this work.</p> <p>*Corresponding authors: <a href="mailto:zhujh@im.ac.cn">zhujh@im.ac.cn</a> (J.Z.), <a href="mailto:erubin@hsph.harvard.edu">erubin@hsph.harvard.edu</a> (E. J. R.)</p> <p><strong> </strong></p> <p><strong>Abstract</strong></p> <p>Proteolysis-targeting chimeras (PROTACs) represent a new therapeutic modality involving selectively directing disease-causing proteins for degradation through proteolytic systems. Our ability to exploit targeted protein degradation (TPD) for antibiotic development remains nascent due to our limited understanding of which bacterial proteins are amenable to a TPD strategy. Here, we use a genetic system to model chemically-induced proximity and degradation to screen essential proteins in <em>Mycobacterium smegmatis </em>(<em>Msm</em>)<em>, </em>a model for the human pathogen <em>M. tuberculosis </em>(<em>Mtb</em>). By integrating experimental screening of 72 protein candidates and machine learning, we find that drug-induced proximity to the bacterial ClpC1P1P2 proteolytic complex leads to the degradation of many endogenous proteins, especially those with disordered termini. Additionally, TPD of essential <em>Msm </em>proteins inhibits bacterial growth and potentiates the effects of existing antimicrobial compounds. Together, our results provide biological principles to select and evaluate attractive targets for future <em>Mtb</em> PROTAC development, as both standalone antibiotics and potentiators of existing antibiotic efficacy.</p> <p> </p>
Human Pleckstrin Homology domain Interacting Protein (PHIP); A Target Enabling Package
<p>SGC Oxford has expressed, purified and crystallized the second bromodomain of PHIP as part of the probe programme. Fragment screening and X-ray crystallography identified binders, some of which optimised to uM affinity. However, molecules with probe properties were not obtained. Consequently it has been decided to put the information generated into the public domain.</p>
Elongation of very long chain fatty acids protein 7 (ELOVL7); A Target Enabling Package
<p>The long-chain fatty acid elongases (ELOVL) catalyse the first rate-limiting step in the two carbon elongation of the acyl chains of fatty acids (FAs) greater than 12 carbons in length. Defects in these ELOVL elongases cause severe genetic diseases, such as Stargardt disease-3 and several ataxias, and knockout studies suggest roles in insulin resistance and hepatic steatosis. This TEP provides the first structural information for this family of enzymes which, coupled with mutagenesis and biophysical studies, demonstrates how substrates and products bind within the active site.</p>
Dehydrogenase E1 and transketolase domain-containing protein 1 (DHTKD1); A Target Enabling Package
<p>Inherited mutations of the <em>GCDH </em>gene for glutaryl-CoA dehydrogenase, catalysing the sixth enzymatic step in lysine catabolism, lead to the rare neurometabolic disorder Glutaric Aciduria type 1 (GA1). There is a rationale that inhibition of the fifth lysine catabolising step, catalysed by the DHTKD1 enzyme, could provide therapeutic benefit for GA1 by means of substrate reduction. This TEP provides early tools to develop DHTKD1 inhibitors, including recombinant protein, structure, biophysical (activity and stability) assays and fragment hits of human DHTKD1. This work also reports the interaction of DHTKD1 with its functional partner DLST as a binary complex, and an EM reconstruction of the DLST catalytic core.</p>
Regional summary statistics for 1107 protein targets based on the Olink technology
<p>This data set contains regional summary statistics (±500kb around the protein coding gene) for a total of 1107 protein - gene combinations as measured by the Olink Proximity Extension Assay in the Fenland study (https://www.mrc-epid.cam.ac.uk/research/studies/fenland/) among 485 individuals. A detailed description of the genetic analysis can be found here https://www.nature.com/articles/s41467-021-27164-0. </p>
Human Kelch-like ECH Associated Protein 1 (KEAP1); A Target Enabling Package
<p>KEAP1 is a highly redox-sensitive member of the BTB-Kelch family that assembles with the CUL3 protein to form a Cullin-RING E3 ligase complex for the degradation of NRF2. Oxidative stress disables KEAP1 allowing NRF2 protein levels to accumulate for the transactivation of critical stress response genes. Consequently, the KEAP1-NRF2 system is a highly attractive target for the development of protein-protein interaction inhibitors that will stabilise NRF2 for therapeutic effect in conditions of neurodegeneration and inflammation. As part of this TEP we have solved the first crystal structure of a KEAP1-CUL3 complex as well as a structure of the apo-Kelch domain suitable for small molecule soaking. We further established a selectivity assay panel of 17 human Kelch domain-containing proteins and have shown that non-covalent KEAP1 inhibitors from the literature are highly selective for KEAP1. This protein panel offers a resource for future work on KEAP1 as well as 16 other human Kelch proteins.</p>
Major facilitator superfamily domain-containing protein 10 (MFSD10) A Target Enabling Package (TEP)
<p>MFSD10 (also known as TETRAN in humans) has been proposed to function as an organic anion efflux pump and as a transporter for some NSAIDs. We have produced milligram quantities of purified recombinant protein and solved its structure in an outward-facing state at 2.6 Å resolution by X-ray crystallography. The structure - the first example for a human atypical SLC - provides the initial clues to understanding the broad specificity of its putative substrate-binding site.</p>
Raw data for "Host-interactor screens of Phytophthora infestans RXLR proteins reveal vesicle trafficking as a major effector-targeted process"
<p>This dataset contains raw and original images, phylogenetic tree files, sequence alignment files used for phylogenetic tree construction and unprocessed data for figures presented in the manuscript titled "Host-interactor screens of <em>Phytophthora infestans</em> RXLR proteins reveal vesicle trafficking as a major effector-targeted process". Each zip file contains raw data for each figure in the manuscript. A version of the manuscript is available on bioRxiv with doi.org/10.1101/2020.09.24.308585.</p>
Data from: Convergent rates of protein evolution identify novel targets of sexual selection in primates
<p>Sexual selection is the differential reproductive success of individuals, resulting from competition for mates, mate choice, or success in fertilization. In primates, this selective pressure often leads to the development of exaggerated traits which play a role in sexual competition and successful reproduction. In order to gain insight into the mechanisms driving the development of sexually selected traits, we used an unbiased genome-wide approach across 21 primate species to correlate individual rates of protein evolution to relative testes size and sexual dimorphism in body size, two anatomical hallmarks of sexual selection in mammals. Among species with presumed high levels of sperm competition, we detected strong conservation of testes-specific proteins responsible for spermatogenesis and ciliary form and function. In contrast, we identified accelerated evolution of female reproductive proteins expressed in the vagina, cervix, and fallopian tubes in these same species. Additionally, we found accelerated protein evolution in lymphoid tissue, indicating that adaptive immune functions may also be influenced by sexual selection. This study demonstrates the distinct complexity of sexual selection in primates revealing contrasting patterns of protein evolution between male and female reproductive tissues.</p>
Small molecules targeting the structural dynamics of AR-V7 partially disordered protein using deep learning and physics based models.
<p>Partially disordered proteins can contain both stable and unstable secondary structure segments and are involved in various (mis)functions in the cell. The extensive conformational dynamics of partially disordered proteins scaling with extent of disorder and length of the protein hampers the efficiency of traditional experimental and in-silico structure-based drug discovery approaches. Therefore new efficient paradigms in drug discovery taking into account conformational ensembles of proteins need to emerge. In this study, using as a test case the AR-V7 transcription factor splicing variant related to prostate cancer, we present an automated methodology that can accelerate the screening of small molecule binders targeting partially disordered proteins. By swiftly identifying the conformational ensemble of AR-V7, and reducing the dimension of binding-sites by a factor of 90 by applying appropriate physicochemical filters, we combine physics based molecular docking and multi-objective classification machine learning models that speed up the screening of thousands of compounds targeting AR-V7 multiple binding sites. Our method not only identifies previously known binding sites of AR-V7, but also discovers new ones, as well as increases the multi-binding site hit-rate of small molecules by a factor of 17 compared to naive physics-based molecular docking. </p>
Pleckstrin Homology domain Interacting Protein (PHIP); A Target Enabling Package
<p>SGC Oxford has expressed, purified and crystallized the second bromodomain of PHIP as part of the probe programme. Fragment screening and X-ray crystallography identified binders, some of which optimised to uM affinity. However, molecules with probe properties were not obtained. Consequently it has been decided to put the information generated into the public domain.</p>
Data from: Convergent rates of protein evolution identify novel targets of sexual selection in primates
Open the record for dataset details and reuse information.
Human Kelch-like Protein 20 (KLHL20); A Target Enabling Package
<p>The BTB-Kelch protein KLHL20 is a hypoxia-induced CUL3-dependent E3 ligase linked to autophagy, Alzheimer’s disease and cancer. KLHL20 acts to terminate autophagy by promoting the ubiquitination and degradation of ULK1. KLHL20 is also reported as a top 20 biomarker for Alzheimer’s disease progression. Inhibition of KLHL20 may be neuroprotective by extending autophagy for the clearance of neurotoxic proteins aggregates. KLHL20 also promotes cancer through the ubiquitination and degradation of tumour suppressors including PML and DAPK1. We have solved the 1.1 Å structure of the Kelch domain of KLHL20 in complex with a DAPK1 peptide. We have used biophysical and cellular studies to validate this peptide site as a degron site for DAPK1 degradation. Using this peptide, we have also established alpha screen and HTRF assays to identify potent small molecule covalent inhibitors that compete with DAPK1 for binding to the Kelch domain of KLHL20.</p>
Dataset for MD and MM/GBSA-Based Evalulation of Ternary Complexes Induced by Proteolysis Targeting Chimeras (PROTACs) for Targeted Protein Degradation
<p>This is the dataset for all input files, output files/results, and submit script or its templates for running the MD and MMGBSA calculations in the paper. Four compressed archives represent the 4 systems we ran our simulations on. The general workflow for all systems follow the sequence of, after starting pose generated by protein docking, the starting frame for MD and its parameter file is generated in the Tleap folder; the MD trajectories are found in the PMEMD folders; and the energy calculations are found in the MMGBSA folders.</p>
Trypanosoma brucei bloodstream form tagging: Targeted subcellular protein localisation.
<p>Trypanosoma brucei bloodstream form tagging protein localisation data. Widefield epifluorescence microscope images of protein subcellular localisation in the bloodstream form life cycle stage of the unicellular eukaryotic pathogen Trypanosoma brucei by endogenous tagging with mNeonGreen (mNG). This master deposition includes a summary of the localisations, primer sequences and DOI indexing, provided in a directory structure analogous to the TrypTag genome-wide procyclic form project: <a href="https://doi.org/10.5281/zenodo.6862298">https://doi.org/10.5281/zenodo.6862298</a> It does not include any microscopy data, which are spread over multiple Zenodo DOIs. Instead, this deposition and the raw and processed data directories include an index to each DOI.</p> <p><strong>localisations.tsv</strong><br> Tab-delimited table, which can be opened in Excel, of localisation annotations for each gene tagged. Also includes primer sequences used, the 96 well plate in which tagging was carried out organised with one row per gene ID, with sets of columns for N and C terminal tagging.</p> <p><strong>geneselection.tsv</strong><br> Tab-delimited table of criteria used for gene selection for tagging. This includes presence/absence of a <em>Leishmania major </em>or <em>Trypanosoma cruzi </em>ortholog, localisation and signal intensity by procyclic form tagging (TrypTag) and upregulation at mRNA level.</p> <p><strong>id_doi_index.tsv</strong><br> Tab-delimited table listing all Trypanosoma brucei Lister 427 gene IDs, if tagging was attempted at the N or C terminus and, if so, the Zenodo DOI at which to find the microscopy data. To download data for a particular gene ID, find its entry in this table, go to the corresponding Zenodo DOI and download <plateid_date>.zip for the raw microscopy data or <plateid_date>_processed.zip for the processed microscopy data. In the latter, images are named by gene ID and tagged terminus.</p> <p><strong>plate_doi_index.tsv</strong><br> Tab-delimited table listing all 96 plates which were part of the targeted bloodstream form tagging project and the Zenodo DOI at which the data can be found. Downloading the data from all of these Zenodo DOIs gives the full microscopy dataset.</p> <p><strong>trypTag_BSF_master.zip</strong><br> Zip file containing the master directory structure for the targeted bloodstream form tagging project database. This contains all internal code which was used to build the bloodstream form tagging database from the raw microscopy data.</p> <p><strong>readme.docx</strong><br> Documentation on data access and rebuilding the database using trypTag_BSF_master.zip</p>
Condensate targeting as a strategy to prevent irreversible protein aggregation: implications for ALS and FTD | Talk - I PhasAGE International Conference
<p>The <strong>I PhasAGE international conference</strong> brought together members of the PhasAGE consortium as well as outstanding international speakers showcasing high impact achievements in the field of liquid-liquid phase separation in aging and late-onset diseases.</p> <p>For details on conference program please see: https://phasage.eu/phasage-conference-1/ </p>
In vivo characterization of antibodies directed against TREAT-AD target proteins in mouse model of AD pathology
<p><em>In vivo </em>characterization of antibodies directed against TREAT-AD target proteins (Moesin, CD44, Midkine, and SFRP1) in the 5xFAD mouse model</p>
Substrates and a novel component in hSnd2-dependent ER protein targeting
<p>Protein import into the endoplasmic reticulum (ER) is essential for about 30% of the human proteome. It involves targeting of precursor proteins to the ER and insertion into or translocation across the ER membrane. Furthermore, it relies on signals in the precursor polypeptides and components, which read the signals and facilitate their targeting to a protein-conducting channel in the ER membrane, the Sec61 complex. Compared to the SRP- and TRC-dependent pathways, little is known about the SRP-independent/SND pathway. Our aim was to identify additional components and characterize the client spectrum of the human SND pathway. The established strategy of combining depletion of the central hSnd2-component from HeLa cells with proteomic- and differential protein abundance-analysis was used. The SRP and TRC targeting pathways were analyzed in comparison. TMEM109 was characterized as hSnd3. Unlike SRP but similar to TRC, the SND clients are predominantly membrane proteins with N-terminal, central, or C-terminal targeting signals.</p>
Chromatin Accessibility Plays a Key Role in Selective Targeting of Hox Proteins
<p>Supplementary data tables for bioRxiv preprint "Chromatin Accessibility Plays a Key Role in Selective Targeting of Hox Proteins "</p> <p>All tables as Tab Delimited Text files</p>
Activity-based proteomics reveals nine target proteases for the recombinant protein-stabilizing inhibitor SlCYS8 in Nicotiana benthamiana
<p>Complete dataset (MS Label-free quantification) for the publication 'Activity-based proteomics reveals nine target proteases for the recombinant protein-stabilizing inhibitor <em>Sl</em>CYS8 in <em>Nicotiana benthamiana</em>'</p> <p>DOI: 10.1111/pbi.13092</p> <p> </p>
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Allen Brain Atlas
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DANDI Archive for NWB datasets
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International Brain Laboratory public data
The International Brain Laboratory public data releases expose standardized mouse decision-making experiments, including Neuropixels recordings, widefield calcium imaging, behavior, and session metadata accessed through the ONE API.
OpenNeuro
OpenNeuro is a free, open platform for sharing neuroimaging datasets, with public search, dataset pages, and download paths for web, S3, DataLad, and the OpenNeuro CLI.