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Drug Development.
Alzheimers Dement
December 2024
Washington University School of Medicine, St. Louis, MO, USA.
Background: Alzheimer's disease neuropathology involves the deposition in brain of aggregates enriched with microtubule-binding-region (MTBR) of tau adopting an abnormal conformation between residues 306-378 in the core of aggregates. Anti-tau drugs targeting around this domain have the potential to interfere with the cell-to-cell propagation of pathological tau. Bepranemab is a humanized monoclonal Ig4 antibody binding to tau residues 235-250.
View Article and Find Full Text PDFDrug Development.
Alzheimers Dement
December 2024
Yonsei University, Incheon, Incheon, Korea, Republic of (South).
Background: As amyloid-β (Aβ) aggregates are considered as the biomarkers and key factors in the pathology of Alzheimer's disease, there has been extensive investigation into Aβ-targeting compounds for the development of diagnostics and drug discovery related to the disorder. However, the polymorphic and heterogenous nature of Aβ aggregates impedes the structural understanding of their structure. Consequently it is a major challenge to develop new diagnostic and therapeutic development of AD and to study the mechanism of Aβ-targeting compounds.
View Article and Find Full Text PDFInherent asymmetry of Rpd3S coordinates its nucleosome engagement and association with elongating RNA polymerase II.
Nat Struct Mol Biol
January 2025
Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
The Rpd3S histone deacetylase complex has a crucial role in genomic integrity by deacetylating transcribed nucleosomes following RNA polymerase (Pol) II passage. Cryo-EM studies highlight the importance of asymmetrical Rco1-Eaf3 dimers in nucleosome binding, yet the interaction dynamics with nucleosomal substrates alongside elongating Pol II are poorly understood. Here we demonstrate the essential function of the Rco1 N-terminal intrinsically disordered region (IDR) in modulating Pol II association, in which K/R mutations within the Rco1 IDR impair interaction of Rpd3S with the C-terminal domain (CTD) of Rpb1, without affecting nucleosome recognition or complex integrity.
View Article and Find Full Text PDFBiochemical and structural characterization of Rab3GAP reveals insights into Rab18 nucleotide exchange activity.
Nat Commun
January 2025
Life Sciences Institute, Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
The heterodimeric Rab3GAP complex is a guanine nucleotide exchange factor (GEF) for the Rab18 GTPase that regulates lipid droplet metabolism, ER-to-Golgi trafficking, secretion, and autophagy. Why both subunits of Rab3GAP are required for Rab18 GEF activity and the molecular basis of how Rab3GAP engages and activates its cognate substrate are unknown. Here we show that human Rab3GAP is conformationally flexible and potentially autoinhibited by the C-terminal domain of its Rab3GAP2 subunit.
View Article and Find Full Text PDFMolecular mechanisms underlying allosteric behavior of Escherichia coli DgoR, a GntR/FadR family transcriptional regulator.
Nucleic Acids Res
January 2025
Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Sector 81, Knowledge City, SAS Nagar, Mohali 140306, Punjab, India.
GntR/FadR family featuring an N-terminal winged helix-turn-helix DNA-binding domain and a C-terminal α-helical effector-binding and oligomerization domain constitutes one of the largest families of transcriptional regulators. Several GntR/FadR regulators govern the metabolism of sugar acids, carbon sources implicated in bacterial-host interactions. Although effectors are known for a few sugar acid regulators, the unavailability of relevant structures has left their allosteric mechanism unexplored.
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