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Nature Structural & Molecular Biology

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https://www.readbyqxmd.com/read/29760531/the-reactivity-driven-biochemical-mechanism-of-covalent-kras-g12c-inhibitors
#1
Rasmus Hansen, Ulf Peters, Anjali Babbar, Yuching Chen, Jun Feng, Matthew R Janes, Lian-Sheng Li, Pingda Ren, Yi Liu, Patrick P Zarrinkar
Activating mutations in KRAS are among the most common tumor driver mutations. Until recently, KRAS had been considered undruggable with small molecules; the discovery of the covalent KRASG12C inhibitors ARS-853 and ARS-1620 has demonstrated that it is feasible to inhibit KRAS with high potency in cells and animals. Although the biological activity of these inhibitors has been described, the biochemical mechanism of how the compounds achieve potent inhibition remained incompletely understood. We now show that the activity of ARS-853 and ARS-1620 is primarily driven by KRAS-mediated catalysis of the chemical reaction with Cys12 in human KRASG12C , while the reversible binding affinity is weak, in the hundreds of micromolar or higher range...
May 14, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29760530/let-k-ras-activate-its-own-inhibitor
#2
Alexander V Statsyuk
No abstract text is available yet for this article.
May 14, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29735995/rbr-ligase-mediated-ubiquitin-transfer-a-tale-with-many-twists-and-turns
#3
REVIEW
Helen Walden, Katrin Rittinger
RBR ligases are an enigmatic class of E3 ubiquitin ligases that combine properties of RING and HECT-type E3s and undergo multilevel regulation through autoinhibition, post-translational modifications, multimerization and interaction with binding partners. Here, we summarize recent progress in RBR structures and function, which has uncovered commonalities in the mechanisms by which different family members transfer ubiquitin through a multistep process. However, these studies have also highlighted clear differences in the activity of different family members, suggesting that each RBR ligase has evolved specific properties to fit the biological process it regulates...
May 7, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29686279/iron-homeostasis-regulates-facultative-heterochromatin-assembly-in-adaptive-genome-control
#4
Pamela S Gallagher, Madeline Larkin, Gobi Thillainadesan, Jothy Dhakshnamoorthy, Vanivilasini Balachandran, Hua Xiao, Christopher Wellman, Raghunath Chatterjee, David Wheeler, Shiv I S Grewal
Iron metabolism is critical for sustaining life and maintaining human health. Here, we find that iron homeostasis is linked to facultative heterochromatin assembly and regulation of gene expression during adaptive genome control. We show that the fission yeast Clr4/Suv39h histone methyltransferase is part of a rheostat-like mechanism in which transcriptional upregulation of mRNAs in response to environmental change provides feedback to prevent their uncontrolled expression through heterochromatin assembly. Interestingly, proper iron homeostasis is required, as iron depletion or downregulation of iron transporters causes defects in heterochromatin assembly and unrestrained upregulation of gene expression...
April 23, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29662218/tapping-the-rna-world-for-therapeutics
#5
REVIEW
Judy Lieberman
A recent revolution in RNA biology has led to the identification of new RNA classes with unanticipated functions, new types of RNA modifications, an unexpected multiplicity of alternative transcripts and widespread transcription of extragenic regions. This development in basic RNA biology has spawned a corresponding revolution in RNA-based strategies to generate new types of therapeutics. Here, I review RNA-based drug design and discuss barriers to broader applications and possible ways to overcome them. Because they target nucleic acids rather than proteins, RNA-based drugs promise to greatly extend the domain of 'druggable' targets beyond what can be achieved with small molecules and biologics...
April 16, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29632374/short-cryptic-exons-mediate-recursive-splicing-in-drosophila
#6
Brian Joseph, Shu Kondo, Eric C Lai
Many long Drosophila introns are processed by an unusual recursive strategy. The presence of ~200 adjacent splice acceptor and splice donor sites, termed ratchet points (RPs), were inferred to reflect 'zero-nucleotide exons', whose sequential processing subdivides removal of long host introns. We used CRISPR-Cas9 to disrupt several intronic RPs in Drosophila melanogaster, some of which recapitulated characteristic loss-of-function phenotypes. Unexpectedly, selective disruption of RP splice donors revealed constitutive retention of unannotated short exons...
April 9, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29610494/structural-basis-of-small-molecule-inhibition-of-human-multidrug-transporter-abcg2
#7
Scott M Jackson, Ioannis Manolaridis, Julia Kowal, Melanie Zechner, Nicholas M I Taylor, Manuel Bause, Stefanie Bauer, Ruben Bartholomaeus, Guenther Bernhardt, Burkhard Koenig, Armin Buschauer, Henning Stahlberg, Karl-Heinz Altmann, Kaspar P Locher
ABCG2 is an ATP-binding cassette (ABC) transporter that protects tissues against xenobiotics, affects the pharmacokinetics of drugs and contributes to multidrug resistance. Although many inhibitors and modulators of ABCG2 have been developed, understanding their structure-activity relationship requires high-resolution structural insight. Here, we present cryo-EM structures of human ABCG2 bound to synthetic derivatives of the fumitremorgin C-related inhibitor Ko143 or the multidrug resistance modulator tariquidar...
April 2, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29610493/atomic-structures-of-fus-lc-domain-segments-reveal-bases-for-reversible-amyloid-fibril-formation
#8
Feng Luo, Xinrui Gui, Heng Zhou, Jinge Gu, Yichen Li, Xiangyu Liu, Minglei Zhao, Dan Li, Xueming Li, Cong Liu
Thermostable cross-β structures are characteristic of pathological amyloid fibrils, but these structures cannot explain the reversible nature of fibrils formed by RNA-binding proteins such as fused in sarcoma (FUS), involved in RNA granule assembly. Here, we find that two tandem (S/G)Y(S/G) motifs of the human FUS low-complexity domain (FUS LC) form reversible fibrils in a temperature- and phosphorylation-dependent manner. We named these motifs reversible amyloid cores, or RAC1 and RAC2, and determined their atomic structures in fibrillar forms, using microelectron and X-ray diffraction techniques...
April 2, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29610492/g%C3%A3-nter-blobel-1936-2018
#9
Yuh Min Chook, Beatriz M A Fontoura, Michael P Rout
No abstract text is available yet for this article.
April 2, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29581568/author-correction-global-delay-in-nascent-strand-dna-methylation
#10
Jocelyn Charlton, Timothy L Downing, Zachary D Smith, Hongcang Gu, Kendell Clement, Ramona Pop, Veronika Akopian, Sven Klages, David P Santos, Alexander M Tsankov, Bernd Timmermann, Michael J Ziller, Evangelos Kiskinis, Andreas Gnirke, Alexander Meissner
Following online publication of this article, the Gene Expression Omnibus records corresponding to accession codes GSM2406773, MN-d6, and GSM2406772, MN-d14, listed in the data availability statement were deleted. The data are now available under accession codes GSM3039355, WGBS_hESC_WT_D6_R4 (MN day 6), and GSM3039351, WGBS_hESC_WT_D14_R4 (MN day 14), and the data availability statement has been updated with the new accession codes in the HTML and PDF versions of the article.
March 26, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29581567/gating-interaction-maps-reveal-a-noncanonical-electromechanical-coupling-mode-in-the-shaker-k-channel
#11
Ana I Fernández-Mariño, Tyler J Harpole, Kevin Oelstrom, Lucie Delemotte, Baron Chanda
Membrane potential regulates the activity of voltage-dependent ion channels via specialized voltage-sensing modules, but the mechanisms involved in coupling voltage-sensor movement to pore opening remain unclear owing to a lack of resting state structures and robust methods to identify allosteric pathways. Here, using a newly developed interaction-energy analysis, we probe the interfaces of the voltage-sensing and pore modules in the Drosophila Shaker K+ channel. Our measurements reveal unexpectedly strong equilibrium gating interactions between contacts at the S4 and S5 helices in addition to those between S6 and the S4-S5 linker...
March 26, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29555971/molecular-autopsy-provides-evidence-for-widespread-ribosome-phased-mrna-fragmentation
#12
Tatsuaki Kurosaki, Lynne E Maquat
No abstract text is available yet for this article.
March 19, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29540792/author-correction-structural-basis-of-aauaaa-polyadenylation-signal-recognition-by-the-human-cpsf-complex
#13
Marcello Clerici, Marco Faini, Lena M Muckenfuss, Ruedi Aebersold, Martin Jinek
In the version of this article initially published online, an incorrect accession code PDB 6FN9 was introduced in Methods, in the 'Model building' section, line 2. This has been corrected to PDB 6F9N. The error has been corrected in the PDF and HTML versions of this article.
March 14, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29531287/atomic-level-evidence-for-packing-and-positional-amyloid-polymorphism-by-segment-from-tdp-43-rrm2
#14
Elizabeth L Guenther, Peng Ge, Hamilton Trinh, Michael R Sawaya, Duilio Cascio, David R Boyer, Tamir Gonen, Z Hong Zhou, David S Eisenberg
Proteins in the fibrous amyloid state are a major hallmark of neurodegenerative disease. Understanding the multiple conformations, or polymorphs, of amyloid proteins at the molecular level is a challenge of amyloid research. Here, we detail the wide range of polymorphs formed by a segment of human TAR DNA-binding protein 43 (TDP-43) as a model for the polymorphic capabilities of pathological amyloid aggregation. Using X-ray diffraction, microelectron diffraction (MicroED) and single-particle cryo-EM, we show that the247 DLIIKGISVHI257 segment from the second RNA-recognition motif (RRM2) forms an array of amyloid polymorphs...
March 12, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29728656/conformational-plasticity-in-the-selectivity-filter-of-the-trpv2-ion-channel
#15
Lejla Zubcevic, Son Le, Huanghe Yang, Seok-Yong Lee
Transient receptor potential vanilloid (TRPV) channels are activated by ligands and heat and are involved in various physiological processes. In contrast to the architecturally related voltage-gated cation channels, TRPV1 and TRPV2 subtypes possess another activation gate at the selectivity filter that can open widely enough to permeate large organic cations. Despite recent structural advances, the mechanism of selectivity filter gating and permeation for both metal ions and large molecules by TRPV1 or TRPV2 is not well known...
May 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29728655/high-performance-virtual-screening-by-targeting-a-high-resolution-rna-dynamic-ensemble
#16
Laura R Ganser, Janghyun Lee, Atul Rangadurai, Dawn K Merriman, Megan L Kelly, Aman D Kansal, Bharathwaj Sathyamoorthy, Hashim M Al-Hashimi
Dynamic ensembles hold great promise in advancing RNA-targeted drug discovery. Here we subjected the transactivation response element (TAR) RNA from human immunodeficiency virus type-1 to experimental high-throughput screening against ~100,000 drug-like small molecules. Results were augmented with 170 known TAR-binding molecules and used to generate sublibraries optimized for evaluating enrichment when virtually screening a dynamic ensemble of TAR determined by combining NMR spectroscopy data and molecular dynamics simulations...
May 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29728654/structural-basis-for-membrane-anchoring-and-fusion-regulation-of-the-herpes-simplex-virus-fusogen-gb
#17
Rebecca S Cooper, Elka R Georgieva, Peter P Borbat, Jack H Freed, Ekaterina E Heldwein
Viral fusogens merge viral and cell membranes during cell penetration. Their ectodomains drive fusion by undergoing large-scale refolding, but little is known about the functionally important regions located within or near the membrane. Here we report the crystal structure of full-length glycoprotein B (gB), the fusogen from herpes simplex virus, complemented by electron spin resonance measurements. The membrane-proximal (MPR), transmembrane (TMD), and cytoplasmic (CTD) domains form a uniquely folded trimeric pedestal beneath the ectodomain, which balances dynamic flexibility with extensive, stabilizing membrane interactions...
May 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29728653/mapping-interactions-with-the-chaperone-network-reveals-factors-that-protect-against-tau-aggregation
#18
Sue-Ann Mok, Carlo Condello, Rebecca Freilich, Anne Gillies, Taylor Arhar, Javier Oroz, Harindranath Kadavath, Olivier Julien, Victoria A Assimon, Jennifer N Rauch, Bryan M Dunyak, Jungsoon Lee, Francis T F Tsai, Mark R Wilson, Markus Zweckstetter, Chad A Dickey, Jason E Gestwicki
A network of molecular chaperones is known to bind proteins ('clients') and balance their folding, function and turnover. However, it is often unclear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein-aggregation diseases. Here, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ~30 purified chaperones and ~20 disease-associated tau variants (~600 combinations)...
May 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29728652/defective-germline-reprogramming-rewires-the-spermatogonial-transcriptome
#19
Lina Vasiliauskaitė, Rebecca V Berrens, Ivayla Ivanova, Claudia Carrieri, Wolf Reik, Anton J Enright, Dónal O'Carroll
Defective germline reprogramming in Piwil4 (Miwi2)- and Dnmt3l-deficient mice results in the failure to reestablish transposon silencing, meiotic arrest and progressive loss of spermatogonia. Here we sought to understand the molecular basis for this spermatogonial dysfunction. Through a combination of imaging, conditional genetics and transcriptome analysis, we demonstrate that germ cell elimination in the respective mutants arises as a result of defective de novo genome methylation during reprogramming rather than because of a function for the respective factors within spermatogonia...
May 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29622787/mechanisms-of-improved-specificity-of-engineered-cas9s-revealed-by-single-molecule-fret-analysis
#20
Digvijay Singh, Yanbo Wang, John Mallon, Olivia Yang, Jingyi Fei, Anustup Poddar, Damon Ceylan, Scott Bailey, Taekjip Ha
Cas9 (from Streptococcus pyogenes) in complex with a guide RNA targets complementary DNA for cleavage. Here, we developed a single-molecule FRET analysis to study the mechanisms of specificity enhancement of two engineered Cas9s (eCas9 and Cas9-HF1). A DNA-unwinding assay showed that mismatches affect cleavage reactions through rebalancing the unwinding-rewinding equilibrium. Increasing PAM-distal mismatches facilitates rewinding, and the associated cleavage impairment shows that cleavage proceeds from the unwound state...
April 2018: Nature Structural & Molecular Biology
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