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Structure, function and regulation of the hsp90 machinery
Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone which is essential in eukaryotes. It is required for the activation and stabilization of a wide variety of client proteins and many of them are involved in important cellular pathways. Since Hsp90 affects numerous physiological processes such as signal transduction, intracellular transport, and protein degradation, it became an interesting target for cancer therapy. Structurally, Hsp90 is a flexible dimeric protein composed of three different domains which adopt structurally distinct conformations. ATP binding triggers directionality in these conformational changes and leads to a more compact state. To achieve its function, Hsp90 works together with a large group of cofactors, termed co-chaperones. Co-chaperones form defined binary or ternary complexes with Hsp90, which facilitate the maturation of client proteins. In addition, posttranslational modifications of Hsp90, such as phosphorylation and acetylation, provide another level of regulation. They influence the conformational cycle, co-chaperone interaction, and inter-domain communications. In this review, we discuss the recent progress made in understanding the Hsp90 machinery.
Journal Article
Principles of nucleic acid structure
This unique and practical resource provides the most complete and concise summary of underlying principles and approaches to studying nucleic acid structure, including discussion of x-ray crystallography, NMR, molecular modelling, and databases.
eBook
Three-dimensional genome structures of single diploid human cells
Beyond the sequence of the genome, its three-dimensional structure is important in regulating gene expression. To understand cell-to-cell variation, the structure needs to be understood at a single-cell level. Chromatin conformation capture methods have allowed characterization of genome structure in haploid cells. Now, Tan et al. report a method called Dip-C that allows them to reconstruct the genome structures of single diploid human cells. Their examination of different cell types highlights the tissue dependence of three-dimensional genome structures. Science , this issue p. 924 A single-cell chromatin conformation capture method employs transposon-based whole-genome amplification to detect chromatin contacts. Three-dimensional genome structures play a key role in gene regulation and cell functions. Characterization of genome structures necessitates single-cell measurements. This has been achieved for haploid cells but has remained a challenge for diploid cells. We developed a single-cell chromatin conformation capture method, termed Dip-C, that combines a transposon-based whole-genome amplification method to detect many chromatin contacts, called META (multiplex end-tagging amplification), and an algorithm to impute the two chromosome haplotypes linked by each contact. We reconstructed the genome structures of single diploid human cells from a lymphoblastoid cell line and from primary blood cells with high spatial resolution, locating specific single-nucleotide and copy number variations in the nucleus. The two alleles of imprinted loci and the two X chromosomes were structurally different. Cells of different types displayed statistically distinct genome structures. Such structural cell typing is crucial for understanding cell functions.
Journal Article
An extended conformation of SARS-CoV-2 main protease reveals allosteric targets
The coronavirus main protease (Mpro) is required for viral replication and has enzymatical activity as a homodimer. Thus, targeting its dimerization is an effective strategy for developing allosteric inhibitors to suppress mutation escape. In this study, we obtained the extended conformation of the native monomer of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Mpro by trapping it with nanobodies, and found that the catalytic domain and the helix domain dissociate, revealing allosteric targets. We also found another state, a compact conformation, similar to the dimeric form. Our data support that the Mpro may be in equilibrium among the monomeric extended conformation as the precursor of all other states, the compact conformation as the intermediate state, and the dimeric conformation as the active state. We designed an innovative Nanoluc Binary Technology (NanoBiT)-based high-throughput allosteric inhibitor assay based on the rearranged conformation. In addition, we identified a set of allosteric inhibitory nanobodies against Mpro, one of which is also a competitive inhibitor of Mpro. Our results provide insight into the maturation of the coronavirus Mpro and a way to develop anticoronaviral drugs through targeting the folding process to inhibit the autocleavage of the main protease.
Journal Article
FAN-C: a feature-rich framework for the analysis and visualisation of chromosome conformation capture data
Chromosome conformation capture data, particularly from high-throughput approaches such as Hi-C, are typically very complex to analyse. Existing analysis tools are often single-purpose, or limited in compatibility to a small number of data formats, frequently making Hi-C analyses tedious and time-consuming. Here, we present FAN-C, an easy-to-use command-line tool and powerful Python API with a broad feature set covering matrix generation, analysis, and visualisation for C-like data (
https://github.com/vaquerizaslab/fanc
). Due to its compatibility with the most prevalent Hi-C storage formats, FAN-C can be used in combination with a large number of existing analysis tools, thus greatly simplifying Hi-C matrix analysis.
Journal Article