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.
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. Its focus is on a survey of structures especially important for biomedical research and pharmacological applications. To aid novices, the book includes an introduction to technical lingo used to describe nucleic acid structure and conformations (roll, slide, twist, buckle, etc.). This completely updated edition features expanded coverage of the latest advances relevant to recognition of DNA and RNA by small molecules and proteins. In particular, the reader will find extensive new discussions on: RNA folding, ribosome structure and antibiotic interactions, DNA quadruplexes, DNA and RNA protein complexes, and short interfering RNA (siRNA). This handy guide ends with a complete list of resources, including relevant online databases and software. * Completely updated with expanded discussion of topics such as RNA folding, ribosome structure and antibiotic interactions, DNA quadruplexes, DNA and RNA protein complexes, and short interfering RNA (siRNA) * Includes a complete list of resources, including relevant online databases and software * Defines technical lingo for novices.
A new (1a6)-linked thiodisaccharide formed by two galactofuranosyl units has been synthesized. Methyl (methyl I-,I2-d-galactofuranosid)uronate was employed as the starting compound, which was ...per-O-silylated with TBSCl and reduced with LiAlH4 to afford methyl 2,3,5-tri-O-tert-butyldimethylsilyl-I2-d-galactofuranoside (2I2) as a key precursor for the preparation of methyl per-O-tert-butyldimethylsilyl-6-thio-I2-d-galactofuranoside (12). The free thiol group of 12 was glycosylated and the product O-deprotected to afford the target I2-d-Galf-S-(1a6)-I2-d-Galf-OMe (14). The conformations of this thiodisaccharide were preliminarily studied using combined theoretical calculations and NMR data. Furthermore, the glycomimetic 14 showed to be a competitive inhibitor of the I2-galactofuranosidase from Penicillum fellutanum (Ki = 3.62 mM).
The luminescence of DNA-bound Ru(phen) sub(2)dppz super(2+) is shown to be highly sensitive to environmental conditions such as ionic strength, temperature, and the sequence and secondary structure ...of the nucleic acid, although not to bulky DNA substituents in the major groove. Each enantiomer has two characteristic lifetimes with any polynucleotide and their relative amplitudes vary as a function of binding ratio. For poly(dA-dT) sub(2) as a model sequence, the longer lifetime for Delta -Ru(phen) sub(2)dppz super(2+) has been assigned to canted intercalation of the complex and the shorter lifetime is ascribed to symmetric intercalation. At a fixed binding ratio, the longer lifetime amplitude increases with increasing ionic strength, without significant change in lifetimes. Increasing temperature has a similar effect, but also affects lifetimes. In general, emission is strongest with AT-rich polynucleotides and with higher-order secondary structures, with intensity increasing as single-stranded < duplex < triplex. However, sequence-context and secondary duplex structure also influence the photophysics since emission with poly(dA).poly(dT) is significantly higher than with poly(dA-dT) sub(2) or poly(rA).poly(rU). The strong influence of different environmental conditions on the emission of nucleic acid-bound Ru(phen) sub(2)dppz super(2+) reflects subtle heterogeneities that are inherent elements of DNA recognition by small molecules, amplified by large changes in photophysics caused by differential exposure of the dppz nitrogens to groove hydration.
Abstract
The Protein Data Bank (PDB) is the single global archive of experimentally determined three-dimensional (3D) structure data of biological macromolecules. Since 2003, the PDB has been managed ...by the Worldwide Protein Data Bank (wwPDB; wwpdb.org), an international consortium that collaboratively oversees deposition, validation, biocuration, and open access dissemination of 3D macromolecular structure data. The PDB Core Archive houses 3D atomic coordinates of more than 144 000 structural models of proteins, DNA/RNA, and their complexes with metals and small molecules and related experimental data and metadata. Structure and experimental data/metadata are also stored in the PDB Core Archive using the readily extensible wwPDB PDBx/mmCIF master data format, which will continue to evolve as data/metadata from new experimental techniques and structure determination methods are incorporated by the wwPDB. Impacts of the recently developed universal wwPDB OneDep deposition/validation/biocuration system and various methods-specific wwPDB Validation Task Forces on improving the quality of structures and data housed in the PDB Core Archive are described together with current challenges and future plans.
Transcription factors (TFs) bind DNA in a sequence-specific manner and thereby serve as the protein anchors and determinants of 3D genome organization. Conversely, chromatin conformation shapes TF ...activity, for example, by looping TF-bound enhancers to distally located target genes. Despite considerable effort, our understanding of the mechanistic relation between TFs and 3D genome organization remains limited, in large part due to this interdependency. In this review, we summarize the evidence for the diverse mechanisms by which TFs and their activity shape the 3D genome and vice versa. We further highlight outstanding questions and potential approaches for untangling the complex relation between TF activity and the 3D genome.
Transcription factors shape 3D genome organization, which in turn affects transcription factor activity. Kim and Shendure review our current understanding of the mechanisms underlying this interdependency, discuss implications for transcriptional regulation, and propose approaches to address the key questions that remain.
PDF
