Article
Chemistry, Medicinal
Helen E. Aylott, Stephen J. Atkinson, Paul Bamborough, Anna Bassil, Chun-wa Chung, Laurie Gordon, Paola Grandi, James R. J. Gray, Lee A. Harrison, Thomas G. Hayhow, Cassie Messenger, Darren Mitchell, Alexander Phillipou, Alex Preston, Rab K. Prinjha, Francesco Rianjongdee, Inmaculada Rioja, Jonathan T. Seal, Ian D. Wall, Robert J. Watson, James M. Woolven, Emmanuel H. Demont
Summary: This study successfully reduced the genotoxicity risk of GSK046 by replacing the acetamide functionality with a heterocyclic ring, and identified potent, selective, and bioavailable compounds through a structure-based drug design approach.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Abigail E. Burgess, Torsten Kleffmann, Peter D. Mace
Summary: Proper regulation of gene expression relies on specific protein-protein interactions between epigenetic regulators. Mutations in genes encoding these regulators, such as ASXL1, can lead to cancer and developmental disorders. This study provides a molecular mechanism for the interaction between ASXL1 and BRD4, showing that ASXL1 truncation enhances BRD4 recruitment to transcriptional complexes.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Review
Pharmacology & Pharmacy
Adel Mandl, Mark C. Markowski, Michael A. Carducci, Emmanuel S. Antonarakis
Summary: The BET family of proteins are crucial in activating oncogenic networks in different cancers. Therapeutic targeting of BET proteins has shown potential in treating metastatic castration-resistant prostate cancer. However, clinical success has been limited due to treatment-associated toxicities, drug resistance, and a lack of biomarkers.
EXPERT OPINION ON INVESTIGATIONAL DRUGS
(2023)
Article
Biochemistry & Molecular Biology
Mohamad Zandian, Irene P. Chen, Siddappa N. Byrareddy, Danica Galonic Fujimori, Melanie Ott, Tatiana G. Kutateladze
Summary: This article discusses the pathological functions of BET proteins during viral infection, focusing on the mechanisms underlying their direct interactions with viral proteins.
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS
(2022)
Article
Chemistry, Medicinal
Arup Mondal, G. V. T. Swapna, Maria M. Lopez, Laura Klang, Jingzhou Hao, LiChung Ma, Monica J. Roth, Gaetano T. Montelione, Alberto Perez
Summary: Intrinsically disordered regions of proteins often play a crucial role in protein-protein interactions, but the folding-upon-binding nature of these interactions makes it challenging to predict their three-dimensional structures. In this study, a tandem approach combining NMR chemical shift data and molecular simulations was used to determine the structures of peptide-protein complexes. The MELD technique was applied to polypeptide complexes formed with the extraterminal domain (ET) of bromo and extraterminal domain (BET) proteins, which exhibit a high degree of binding plasticity. The hybrid MELD + NMR approach successfully modeled the bound-state conformations and binding poses of moderately tight binders, providing both the 3D structures of peptide-protein complexes and their relative binding affinities.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biochemistry & Molecular Biology
Jiuwei Lu, Jian Fang, Hongtao Zhu, Kimberly Lu Liang, Nelli Khudaverdyan, Jikui Song
Summary: This study reveals the mechanism of allosteric regulation and dynamic assembly of DNMT3B by investigating its cryo-EM structure under different oligomerization states. The interaction between the ADD domain and the MTase domain of DNMT3B forms an autoinhibitory conformation, similar to the previously observed DNMT3A autoinhibition. The PWWP domain and its associated ICF mutation are found to play a role in the allosteric regulation of DNMT3B tetramer, and the bindings of ADD-H3K4me0 and PWWP-H3K36me3 have differential functional impacts on DNMT3B.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Chemistry, Physical
Vijay H. Masand, Meghshyam K. Patil, Nahed Nasser E. El-Sayed, Magdi E. A. Zaki, Zainab Almarhoon, Sami A. Al-Hussain
Summary: Mivebresib analogues show BET family bromodomain binding affinity in the nano-molar range, with further optimizations needed for druglike molecules. QSAR analysis successfully identifies important pharmacophoric features and establishes a statistically acceptable model with high predictive ability, providing valuable insights for future optimizations.
JOURNAL OF MOLECULAR STRUCTURE
(2021)
Article
Biochemistry & Molecular Biology
Hadar Feinberg, Sabine A. F. Jegouzo, Yi Lasanajak, David F. Smith, Kurt Drickamer, William Weis, Maureen E. Taylor
Summary: The human mannose receptor expressed on macrophages and hepatic endothelial cells plays an important role in reducing tissue damage by scavenging released lysosomal enzymes, glycopeptide fragments of collagen, and pathogenic microorganisms. By binding to mannose, fucose, or N-acetylglucosamine (GlcNAc) residues on these targets, the receptor interacts with sugars in a Ca2+-dependent manner through its C-type carbohydrate-recognition domain 4 (CRD4), which has been investigated through glycan array screening and multiple crystal structures. The interactions with monosaccharides and oligosaccharide substructures present in these ligands provide insight into the mechanisms of binding and potential classes of ligands for the mannose receptor.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Oncology
John Hilton, Mihaela Cristea, Sophie Postel-Vinay, Capucine Baldini, Mark Voskoboynik, William Edenfield, Geoffrey Shapiro, Michael L. Cheng, Jacqueline Vuky, Bradley Corr, Sharmila Das, Abraham Apfel, Ke Xu, Martin Kozicki, Keziban Unsal-Kacmaz, Amy Hammell, Guan Wang, Palanikumar Ravindran, Georgia Kollia, Oriana Esposito, Shodeinde Coker, Jennifer R. Diamond
Summary: BMS-986158, an experimental anticancer therapy, can block BET protein function to regulate cancer-related genes and inhibit tumor growth. This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of BMS-986158. Among the different dosing schedules tested, schedule A (5 days on, 2 days off) showed stable drug levels in the blood, preliminary anticancer effects, and a proportional PK profile.
Article
Cell Biology
Qiong Li, Yong-Liang Jiang, Ling-Yun Xia, Yuxing Chen, Cong-Zhao Zhou
Summary: This study elucidated the structure of an assembly intermediate of RuBisCO enzyme in cyanobacteria and discovered that the proteins Raf1 and RbcX facilitate and regulate RuBisCO assembly by controlling the formation of RuBisCO condensates.
Article
Biology
Sang Chul Shin, Jinyoung Park, Kyung Hee Kim, Jung Min Yoon, Jinhong Cho, Byung Hak Ha, Yeonji Oh, Hyunah Choo, Eun Joo Song, Eunice EunKyeong Kim
Summary: This study investigates the functional and biochemical properties of USP47, and reveals that depleting USP47 inhibits cancer cell growth in a p53-dependent manner and that full-length USP47 has higher deubiquitinase activity. Additionally, the study provides molecular details of USP47 regulation, substrate recognition, and potential hotspots for drug discovery.
COMMUNICATIONS BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Sriram Aiyer, G. V. T. Swapna, Li-Chung Ma, Gaohua Liu, Jingzhou Hao, Gordon Chalmers, Brian C. Jacobs, Gaetano T. Montelione, Monica J. Roth
Summary: The ET domain of BRD3 interacts with viral and host proteins through similar beta-sheet formations. N-15 relaxation studies reveal a restricted flexibility in the linker region, affecting its orientation in the protein complexes. The complex of the ET-binding peptide of host NSD3 protein and the BRD3 ET domain shows a different orientation compared to viral protein complexes.
Article
Biochemistry & Molecular Biology
Daniel Krochmal, Yaming Shao, Nan-Sheng Li, Saurja DasGupta, Sandip A. Shelke, Deepak Koirala, Joseph A. Piccirilli
Summary: Ribozymes that react with small-molecule probes have important applications in transcriptomics and chemical biology. This study focuses on a self-alkylating ribozyme and reports its crystal structures, showing a hook-shaped conformation.
NATURE CHEMICAL BIOLOGY
(2022)
Article
Chemistry, Medicinal
Jingjing Chen, Huixin He, Aihuan Wei, Yalei Li, Gang Cheng, Hui Qin, Hanyue Zhong, Hongchun Liu, Meiyu Geng, Aijun Shen, Youhong Hu
Summary: In this study, novel pyrrolopyridone BET degraders were designed and synthesized based on the binding mode between the pyrrolopyridone BET inhibitor and the BRD4 protein. Potent degraders were discovered through structure-activity relationship study on MV-4-11 cells. Modification of warhead on pyrrolopyridone BET degraders significantly regulates the degradation of BRD4 isoform proteins (long and short), resulting in differential cell cycle arrest and apoptosis on MV-4-11 cells. Docking study revealed that fine structural modification of BET degraders may bind with the BD domain of BRD4 protein to engage various surface areas that bind with CRBN.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Microbiology
Guangai Xue, Klaudia Braczyk, Daniel Goncalves-Carneiro, Daria M. Dawidziak, Katarzyna Sanchez, Heley Ong, Yueping Wan, Kaneil K. Zadrozny, Barbie K. Ganser-Pornillos, Paul D. Bieniasz, Owen Pornillos
Summary: Zinc-finger antiviral protein (ZAP) is an antiviral factor that selectively degrades viral RNA. It has been found that ZAP binds to the cellular polynucleotide poly(ADP-ribose) (PAR), which facilitates ZAP-mediated viral mRNA degradation and is associated with RNA stress granules.
Article
Biochemical Research Methods
Kotaro Takano, Shunsuke Arai, Seiji Sakamoto, Hiroshi Ushijima, Takahisa Ikegami, Kazumi Saikusa, Tsuyoshi Konuma, Itaru Hamachi, Satoko Akashi
ANALYTICAL AND BIOANALYTICAL CHEMISTRY
(2020)
Article
Biochemistry & Molecular Biology
Youfen Ma, Bixue Xu, Jia Yu, Lirong Huang, Xiaoping Zeng, Xiangchun Shen, Chunyan Ren, Yaacov Ben-David, Heng Luo
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2020)
Article
Biochemistry & Molecular Biology
Jing Zeng, Yuxuan Wu, Chunyan Ren, Jasmine Bonanno, Anne H. Shen, Devlin Shea, Jason M. Gehrke, Kendell Clement, Kevin Luk, Qiuming Yao, Rachel Kim, Scot A. Wolfe, John P. Manis, Luca Pinello, J. Keith Joung, Daniel E. Bauer
Article
Genetics & Heredity
Eri Imagawa, Tsuyoshi Konuma, Emalyn E. Cork, George A. Diaz, Kimihiko Oishi
Article
Biochemistry & Molecular Biology
Rei Tohda, Hideaki Tanaka, Risa Mutoh, Xuhong Zhang, Young-Ho Lee, Tsuyoshi Konuma, Takahisa Ikegami, Catharina T. Migita, Genji Kurisu
Summary: The study solves the high-resolution crystal structure of soybean HO-1, revealing novel structural components and proposing evolutionary fine-tuning of plant-type HOs for ferredoxin dependency to adapt to dynamic pH changes.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Kenichi Kamata, Kenji Mizutani, Katsuya Takahashi, Roberta Marchetti, Alba Silipo, Christine Addy, Sam-Yong Park, Yuki Fujii, Hideaki Fujita, Tsuyoshi Konuma, Takahisa Ikegami, Yasuhiro Ozeki, Jeremy R. H. Tame
SCIENTIFIC REPORTS
(2020)
Article
Chemistry, Analytical
Waka Sakamoto, Nanako Azegami, Tsuyoshi Konuma, Satoko Akashi
Summary: This study improved the live single-cell MS method and applied it successfully to observe hemoglobin directly sampled from human erythrocytes. By optimizing experimental methods and conditions, native mass spectra of hemoglobin were obtained using only a single erythrocyte, marking the first report of native MS for endogenous proteins using a single intact human cell.
ANALYTICAL CHEMISTRY
(2021)
Article
Cell & Tissue Engineering
Shuquan Rao, Yao Yao, Josias Soares de Brito, Qiuming Yao, Anne H. Shen, Ruth E. Watkinson, Alyssa L. Kennedy, Steven Coyne, Chunyan Ren, Jing Zeng, Anna Victoria Serbin, Sabine Studer, Kaitlyn Ballotti, Chad E. Harris, Kevin Luk, Christian S. Stevens, Myriam Armant, Luca Pinello, Scot A. Wolfe, Roberto Chiarle, Akiko Shimamura, Benhur Lee, Peter E. Newburger, Daniel E. Bauer
Summary: A study used a pooled CRISPR screen to uncover the correlation between ELANE mutations and neutrophil maturation potential, successfully overcoming maturation blockage in patients with congenital neutropenia through gene editing and establishing relevant animal models. Different types of chromosomal variations impact neutrophil maturation, which is crucial for elucidating disease mechanisms and developing universal treatment approaches.
Article
Biochemistry & Molecular Biology
Kazumasa Komura, Teruo Inamoto, Takuya Tsujino, Yusuke Matsui, Tsuyoshi Konuma, Kazuki Nishimura, Taizo Uchimoto, Takeshi Tsutsumi, Tomohisa Matsunaga, Ryoichi Maenosono, Yuki Yoshikawa, Kohei Taniguchi, Tomohito Tanaka, Hirofumi Uehara, Koichi Hirata, Hajime Hirano, Hayahito Nomi, Yoshinobu Hirose, Fumihito Ono, Haruhito Azuma
Summary: Accumulating evidence supports the clinical benefit of chemoradiation therapy (CRT), but mechanisms in CRT-recurrent clones remain unclear. Aberrant BUB1B/BUBR1 expression was identified in CRT-recurrent bladder cancer cells, leading to excessive mutagenic DNA repair through nonhomologous end joining (NHEJ) and interaction with phosphorylated ATM. Inhibition of ATM abrogated CRT-resistant tumor growth, suggesting a novel approach to overcome CRT resistance.
Article
Genetics & Heredity
Fengxia Zhou, Rui Gan, Fan Zhang, Chunyan Ren, Ling Yu, Yu Si, Zhiwei Huang
Summary: Phage-host interaction signal detector (PHISDetector) was developed to predict phage-host interactions by detecting and integrating diverse signals in bacterial and phage genomic sequences. Machine learning models based on PHIS features were used to score the probability of phage-host interactions. The performance of PHISDetector was evaluated on benchmark datasets and application cases, showing superior prediction accuracies compared to other tools.
GENOMICS PROTEOMICS & BIOINFORMATICS
(2022)
Article
Hematology
Atsushi Tanaka, Taizo A. Nakano, Masaki Nomura, Hiromi Yamazaki, Jan P. Bewersdorf, Roger Mulet-Lazaro, Simon Hogg, Bo Liu, Alex Penson, Akihiko Yokoyama, Weijia Zang, Marije Havermans, Miho Koizumi, Yasutaka Hayashi, Hana Cho, Akinori Kanai, Stanley C. Lee, Muran Xiao, Yui Koike, Yifan Zhang, Miki Fukumoto, Yumi Aoyama, Tsuyoshi Konuma, Hiroyoshi Kunimoto, Toshiya Inaba, Hideaki Nakajima, Hiroaki Honda, Hiroshi Kawamoto, Ruud Delwel, Omar Abdel-Wahab, Daichi Inoue
Summary: This study identifies a novel oncogenic RNA-splicing derived isoform of EVI1 that is frequently present in inv(3)/t(3;3) acute myeloid leukemia. It is generated by mutations in the core RNA splicing factor SF3B1, which is commonly cooccurring with inv(3)/t(3;3) genomic alteration. The mutant SF3B1 spliceosome promotes mis-splicing of EVI1 and enhances self-renewal of hematopoietic stem cells, contributing to leukemic transformation.
Article
Biochemistry & Molecular Biology
Keiichi Hata, Naohiro Kobayashi, Keita Sugimura, Weihua Qin, Deis Haxholli, Yoshie Chiba, Sae Yoshimi, Gosuke Hayashi, Hiroki Onoda, Takahisa Ikegami, Christopher B. Mulholland, Atsuya Nishiyama, Makoto Nakanishi, Heinrich Leonhardt, Tsuyoshi Konuma, Kyohei Arita
Summary: This study determined the structure of the mouse UHRF1 plant homeodomain (PHD) complexed with DPPA3 using nuclear magnetic resonance. The results showed that DPPA3 induces alpha-helices upon binding to UHRF1 PHD, leading to stable complex formation through multifaceted interactions. Mutations in the binding interface and unfolding of the DPPA3 helical structure inhibit the binding of UHRF1 and its chromatin localization.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Genetics & Heredity
Eri Imagawa, Latisha Moreta, Vinod K. Misra, Claire Newman, Tsuyoshi Konuma, Kimihiko Oishi
Summary: A mild phenotype including cleft palate, hypotonia, developmental delay, and minor dysmorphisms was observed in a 3-year-old male with a missense RBM10 variant. The variant affected the expression of downstream genes NUMB and TNRC6A through alternative splicing regulation, resulting in non-lethal developmental delays.
JOURNAL OF HUMAN GENETICS
(2023)
Article
Biochemistry & Molecular Biology
Nan Liu, Tsuyoshi Konuma, Rajal Sharma, Deyu Wang, Nan Zhao, Lingling Cao, Ying Ju, Di Liu, Shuai Wang, Almudena Bosch, Yifei Sun, Siwei Zhang, Donglei Ji, Satoru Nagatoishi, Noa Suzuki, Masaki Kikuchi, Masatoshi Wakamori, Chengcheng Zhao, Chunyan Ren, Thomas Jiachi Zhou, Yaoyao Xu, Jamel Meslamani, Shibo Fu, Takashi Umehara, Kouhei Tsumoto, Satoko Akashi, Lei Zeng, Robert G. Roeder, Martin J. Walsh, Qiang Zhang, Ming-Ming Zhou
Summary: Histone lysine acylation, such as acetylation and crotonylation, plays a crucial role in gene transcription, but our understanding has been limited to transcriptional activation. This study reveals that histone H3 lysine 27 crotonylation (H3K27cr) is involved in gene transcriptional repression. The YEATS domain of GAS41 selectively recognizes H3K27cr in chromatin and forms a complex with SIN3A-HDAC1 co-repressors. The proto-oncogenic transcription factor MYC recruits the GAS41/SIN3A-HDAC1 complex to repress genes, including the cell-cycle inhibitor p21.
Article
Biochemical Research Methods
Tsuyoshi Konuma, Jun-ichi Kurita, Takahisa Ikegami
Summary: The relaxation dispersion (rd) of nuclear magnetic resonance provides thermodynamic and kinetic information for molecules with exchanging conformations. We developed a new pulse sequence (AFTAC) that can suppress artifacts in magnetization components and demonstrated its effectiveness in measuring methyl groups. The AFTAC method achieves similar artifact suppression quality in SI, SI2, and SI3 spin systems.
JOURNAL OF MAGNETIC RESONANCE
(2023)