Review
Biochemistry & Molecular Biology
Stephen J. Harwood, Christopher R. Smith, J. David Lawson, John M. Ketcham
Summary: This review focuses on recent strategies to inhibit RAS-signaling by disrupting protein-protein interactions (PPIs) associated with SOS1, RAF, PDE delta, Grb2, and RAS, in hopes to provide therapies for patients with KRAS-mutant driven cancers.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Jiali Yang, Takahiro Mori, Xingxing Wei, Yudai Matsuda, Ikuro Abe
Summary: The novel isomerase NsrQ from Aspergillus novofumigatus plays a key role in the biosynthesis of fungal tetrahydroxanthones by catalyzing a two-step isomerization reaction. Through biochemical and structural characterizations, it was found that NsrQ and its homologue Dcr3 utilize Glu and His residues as acid-base catalysts and important hydrophobic residues for shaping the active site pocket for substrate binding. The crystal structures of NsrQ and Dcr3 revealed their cone-shaped alpha + beta barrel fold and similarities to the nuclear transport factor 2-like superfamily enzymes.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Biology
Tamar Skaist Mehlman, Justin T. Biel, Syeda Maryam Azeem, Elliot R. Nelson, Sakib Hossain, Louise Dunnett, Neil G. Paterson, Alice Douangamath, Romain Talon, Danny Axford, Helen Orins, Frank von Delft, Daniel A. Keedy, Qiang Cui
Summary: Much of our understanding of protein-ligand interactions comes from X-ray crystal structures determined at cryogenic temperature. However, the impact of room-temperature crystallography on protein-ligand complexes is not well understood. Our study shows that at room temperature, fewer ligands bind and often with weaker affinity, but with temperature-dependent differences in binding poses, solvation, binding sites, and protein conformational responses. This work suggests that existing cryo-temperature structures may provide an incomplete picture and highlights the potential of room-temperature crystallography in revealing distinct conformational modes of protein-ligand systems.
Article
Chemistry, Multidisciplinary
Takahiro Mori, Xin Sun, Stanislav Kadlcik, Jiri Janata, Ikuro Abe
Summary: LmbT is a glycosyltransferase enzyme that incorporates the rare amino acid L-ergothioneine (EGT) into secondary metabolites. Our analysis shows that LmbT has promiscuous substrate specificity and exhibits conformational changes upon substrate binding. The interaction between EGT and LmbT is mediated by specific salt-bridge and cation-pi interactions. This study provides structural insights into the S-glycosylation reaction catalyzed by LmbT with EGT.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Multidisciplinary Sciences
Oliver F. Harder, Sarah V. Barrass, Marcel Drabbels, Ulrich J. Lorenz
Summary: Microsecond time-resolved cryo-EM allows for observation of fast protein dynamics, as demonstrated by the contraction of the CCMV capsid induced by a pH jump.
NATURE COMMUNICATIONS
(2023)
Article
Nanoscience & Nanotechnology
Arjun Rana, Chen-Ting Liao, Ezio Iacocca, Ji Zou, Minh Pham, Xingyuan Lu, Emma-Elizabeth Cating Subramanian, Yuan Hung Lo, Sinead A. Ryan, Charles S. Bevis, Robert M. M. Karl Jr, Andrew J. Glaid, Jeffrey Rable, Pratibha Mahale, Joel Hirst, Thomas Ostler, William Liu, Colum M. O'Leary, Young-Sang Yu, Karen Bustillo, Hendrik Ohldag, David A. Shapiro, Sadegh Yazdi, Thomas E. Mallouk, Stanley J. Osher, Henry C. Kapteyn, Vincent H. Crespi, John V. Badding, Yaroslav Tserkovnyak, Margaret M. Murnane, Jianwei Miao
Summary: The researchers successfully created 138 stable magnetic monopoles on a ferromagnetic meta-lattice and used soft X-ray vector ptycho-tomography to determine their magnetization vector and emergent magnetic field. The study found that the distances between monopole-anti-monopole pairs, monopole-monopole pairs, and anti-monopole-anti-monopole pairs were 18.3 +/- 1.6 nm, 36.1 +/- 2.4 nm, and 43.1 +/- 2.0 nm, respectively. This work demonstrates the potential of ferromagnetic meta-lattices as a platform for studying the interactions and dynamics of magnetic monopoles, and the broad application of soft X-ray vector ptycho-tomography for quantitatively imaging 3D vector fields in magnetic and anisotropic materials at the nanoscale.
NATURE NANOTECHNOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Hannah. A. A. Minas, Romain M. M. Francois, Franziska Hemmerling, Amy. E. E. Fraley, Cora. L. L. Dieterich, Simon. H. H. Ruedisser, Roy. A. A. Meoded, Sabrina Collin, Kira. J. J. Weissman, Arnaud Gruez, Jorn Piel
Summary: Modular trans-acyltransferase polyketide synthases (trans-AT PKSs) are enzymatic assembly lines that introduce remarkable chemical diversity into their polyketide products. This study focuses on the lobatamide A PKS, which incorporates a methylated oxime. By analyzing the structure and mutagenesis of the oxygenase, the authors propose a catalysis model and identify key protein-protein interactions. This work expands the biomolecular toolbox for trans-AT PKS engineering and enables the introduction of masked aldehyde functionalities into diverse polyketides.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Review
Pharmacology & Pharmacy
Jiaxing Wang, Duane D. Miller, Wei Li
Summary: This review summarizes the crystal structures of tubulin in complexes with various CBSIs, aiming to facilitate the discovery of new generations of tubulin inhibitors.
DRUG DISCOVERY TODAY
(2022)
Review
Crystallography
Kiyoung Jang, Hyun Gi Kim, Sandi Hnit San Hlaing, MinSoung Kang, Hui-Woog Choe, Yong Ju Kim
Summary: The three-dimensional structure of proteins is determined by analyzing diffraction data collected using X-ray beams. To prevent damage to protein crystals by X-ray beams, cryoprotectants can be used to stabilize the crystals. However, incorrect selection or treatment of cryoprotectants may lead to deterioration in the quality of crystal diffraction data.
Article
Biochemistry & Molecular Biology
Shruti Chatterjee, Shankar V. Kundapura, Aditya J. Basak, Debangshu Mukherjee, Sagarika Dash, Namrata Ganguli, Amit K. Das, Gayatri Mukherjee, Dibyendu Samanta, Udupi A. Ramagopal
Summary: Tuberculosis is a disease caused by Mycobacterium tuberculosis, primarily transmitted through inhaling droplets from infected individuals. Mycobacteria use pathogen-associated molecular patterns (PAMPs) on their surface to enter alveolar macrophages by recognizing pattern recognition receptors on host cells. One important PAMP is the 19 kDa surface antigen LpqH, which plays a critical role in host-pathogen interactions and immune regulation. This study presents the crystal structure of non-acylated LpqH and demonstrates its functionality in inducing apoptosis in human monocytic cell line THP-1. Conservation analysis reveals a patch of conserved residues on the protein surface, potentially involved in binding partner recognition during host-pathogen interaction.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2022)
Review
Chemistry, Multidisciplinary
Qiuran Wang, Sam H. Brooks, Tianchang Liu, Neil C. Tomson
Summary: Cluster complexes have recently been designed with ligand scaffolds specifically tailored to support multinuclear transition metal cores in order to facilitate cooperative small molecule activation. The incorporation of geometric flexibility and redox-active ligands in the ligand design allows for unique small molecule activation modes, providing significant analogies to heterogeneous and metalloenzyme catalysts.
CHEMICAL COMMUNICATIONS
(2021)
Review
Chemistry, Multidisciplinary
Jack L. Bennett, Giang T. H. Nguyen, William A. Donald
Summary: Native mass spectrometry is a powerful method for studying protein-small molecule interactions in drug discovery, providing unique insights into diverse biomolecular systems. This review highlights the applications of native MS in studying small molecule-protein interactions and discusses the quantification of binding properties and structural analysis techniques. Future developments and potential applications of native MS in drug discovery workflows are also discussed.
Article
Chemistry, Multidisciplinary
Abigail R. Orun, Ethan T. Shields, Sara Dmytriw, Ananya Vajapayajula, Caroline K. Slaughter, Christopher D. Snow
Summary: Researchers have designed isoreticular cocrystals as scaffolds for DNA-binding molecules. These cocrystals have tunable DNA-DNA junctions and can accommodate different guest molecules during crystallization. The design principles can be applied to existing cocrystals to develop programmable scaffolds for DNA-binding molecules.
Article
Biotechnology & Applied Microbiology
Guangqi Li, Xuan Zhou, Zhihong Li, Yunpeng Liu, Dongyang Liu, Youzhi Miao, Qun Wan, Ruifu Zhang
Summary: This study characterized and engineered a thermophilic GH10 family xylanase XynAF1 to improve its thermostability, resulting in a 6-fold increase in stability through rational design and saturation mutagenesis. The high-resolution X-ray crystallographic structure of XynAF1 revealed a rigid skeleton contributing to its hyperthermophilic characteristics. The study provides a promising biocatalyst for high-temperature biotechnological applications.
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Sandesh Deshpande, Eric Altermann, Vijayalekshmi Sarojini, J. Shaun Lott, T. Verne Lee
Summary: Nonribosomal peptide synthetases (NRPSs) are multi-modular enzymes that produce various bioactive peptides, with dynamic proteins characterized by extensive interdomain communications. The crystal structure of multidomain fragments of NRPSs has helped elucidate crucial interdomain interactions, including the novel helix-turn-helix motif playing a major role in the interface between the PCP and R domains. This information may provide insights into the peptide termination reaction catalyzed by the R domain and potential implications in engineering NRPSs for synthesizing novel peptide products.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Oncology
Corinna Spohr, Teresa Poggio, Geoffroy Andrieux, Katharina Schoenberger, Nina Cabezas-Wallscheid, Melanie Boerries, Sebastian Halbach, Anna L. Illert, Tilman Brummer
Summary: The presence of internal tandem duplications (ITD) in FMS-like tyrosine kinase 3 (FLT3) combined with DNMT3A mutations in acute myeloid leukemia (AML) leads to poor prognosis. Studies have shown that GAB2 is essential for the development of Flt3-ITD driven AML, with Gab2 deficient mice displaying prolonged survival and reduced pathology. Gab2 increases signaling of receptor tyrosine kinases, promoting AML aggressiveness and drug resistance, making it a promising biomarker and therapeutic target in human AML.
Article
Biochemistry & Molecular Biology
Go Sugahara, Yuji Ishida, Jae Jin Lee, Meng Li, Yasuhito Tanaka, Hyungjin Eoh, Yusuke Higuchi, Takeshi Saito
Summary: This study aimed to define the environmental requirements necessary for maintaining the homeostasis of terminally differentiated hepatocytes. The supplementation of dimethyl sulfoxide (DMSO) was found to be indispensable for mitigating fate deterioration and promoting adaptation to the in vitro environment. Dimethyl sulfone (DMSO2) was identified as a substitute for DMSO, supporting the long-term maintenance of hepatocyte morphology, marker gene expression, and functionality.
Article
Gastroenterology & Hepatology
Gajanan Kendre, Karthikeyan Murugesan, Tilman Brummer, Oreste Segatto, Anna Saborowski, Arndt Vogel
Summary: This study retrospectively analyzed the genomic data of 6,130 patients diagnosed with intrahepatic cholangiocarcinoma (iCCA), and identified seven oncogenic driver genes and their co-mutational patterns. The study also discovered genetic variations and genomic patterns associated with iCCA, which are important for developing effective treatment strategies and predicting mechanisms of resistance.
JOURNAL OF HEPATOLOGY
(2023)
Article
Cell Biology
Lino Rohrer, Corinna Spohr, Carina Beha, Ricarda Griffin, Sandra Braun, Sebastian Halbach, Tilman Brummer
Summary: The dimerization of RAF kinases plays a crucial role in their activation and the activation of the RAS/ERK pathway. Recent studies have developed a split luciferase system to study the homo- and heterodimerization of BRAF, RAF1, and KSR1. It was found that KRAS(G12V) promotes the dimerization of BRAF, while KSR1 can form homo- and KSR1/BRAF heterodimers even in the absence of KRAS(G12V) through a salt bridge between the CC-SAM domain of KSR1 and the BRAF-specific region.
CELL COMMUNICATION AND SIGNALING
(2023)
Article
Oncology
Melanie Langhammer, Julia Schoepf, Timo Jaquet, Katharina Horn, Moritz Angel, Corinna Spohr, Daniel Christen, Franziska Maria Uhl, Tiago Maie, Henrike Jacobi, Thorsten B. Feyerabend, Julia Huber, Marcus Panning, Cassian Sitaru, Ivan Costa, Robert Zeiser, Konrad Aumann, Heiko Becker, Till Braunschweig, Steffen Koschmieder, Khalid Shoumariyeh, Michael Huber, Mirle Schemionek-Reinders, Tilman Brummer, Sebastian Halbach
Summary: The persistence of leukemic stem cells (LSCs) in chronic myeloid leukemia (CML) presents a challenge in therapy. This study investigates the role of mast cells (MCs) in CML progression and suggests targeting MCs as an additional approach for CML treatment. The BCR::ABL1 fusion gene drives the expansion of bone marrow-derived MCs and enhances their responsiveness to degranulation triggers. In CML patients, splenomegaly is associated with increased BM MC counts and elevated pro-inflammatory cytokines, indicating the importance of MCs in disease progression.
Article
Oncology
Marlene Langenbach, Sophie Giesler, Stefan Richtsfeld, Sara Costa-Pereira, Lukas Rindlisbacher, Tobias Wertheimer, Lukas M. Braun, Geoffroy Andrieux, Sandra Duquesne, Dietmar Pfeifer, Nadine M. Woessner, Hans D. Menssen, Sanaz Taromi, Justus Duyster, Melani Boerries, Tilman Brummer, Bruce R. Blazar, Susana Minguet, Patrick Turko, Mitchell P. Levesque, Burkhard Becher, Rober Zeiser
Summary: Treatment of metastatic melanoma with immune checkpoint inhibitors (ICI) has high response rates, but resistance to ICI impacts patient survival. In this study, the role of MDM2 inhibition in enhancing ICI therapy was investigated using mouse models and patient-derived melanoma cells. MDM2 inhibition induced expression of IL15 and MHC-II in melanoma cells through p53 induction. This enhanced antitumor immunity and induced anti-melanoma immune memory. In patients, increased IL15 and MHC-II expression correlated with better prognosis in WT melanoma but not TP53-mutated melanoma.
MOLECULAR CANCER RESEARCH
(2023)
Meeting Abstract
Oncology
Romain Sigaud, Anja Stefanski, Florian Selt, Thomas Hielscher, Diren Usta, Daniela Kocher, Daniel Picard, Isabel Budenbender, Marc Remke, Stefan M. Pfister, David T. W. Jones, Tilman Brummer, Olaf Witt, Till Milde
Meeting Abstract
Oncology
Romain Sigaud, Thomas K. Albert, Caroline Hess, Thomas Hielscher, Nadine Winkler, Carolin Walter, Daniel Muenter, Florian Selt, Diren Usta, Jonas Ecker, Angela Brentrup, Martin Hasselblatt, Christian Thomas, Julian Varghese, David Capper, Ulrich W. Thomale, Pablo Hernaiz Driever, Michele Simon, Svea Horn, Nina Annika Herz, Arend Koch, Felix Sahm, Stefan Hamel Mann, Augusto Faria Andrade, Nada Jabado, Antoinette Y. N. Schouten-van Meeteren, Eelco Hoving, Tilman Brummer, Cornelis M. van Tilburg, Stefan M. Pfister, Olaf Witt, David T. W. Jones, Kornelius Kerl, Till Milde
Article
Multidisciplinary Sciences
Romain Sigaud, Thomas K. Albert, Caroline Hess, Thomas Hielscher, Nadine Winkler, Daniela Kocher, Carolin Walter, Daniel Muenter, Florian Selt, Diren Usta, Jonas Ecker, Angela Brentrup, Martin Hasselblatt, Christian Thomas, Julian Varghese, David Capper, Ulrich W. Thomale, Pablo Hernaiz Driever, Michele Simon, Svea Horn, Nina Annika Herz, Arend Koch, Felix Sahm, Stefan Hamelmann, Augusto Faria-Andrade, Nada Jabado, Martin U. Schuhmann, Antoinette Y. N. Schouten-van Meeteren, Eelco Hoving, Tilman Brummer, Cornelis M. van Tilburg, Stefan M. Pfister, Olaf Witt, David T. W. Jones, Kornelius Kerl, Till Milde
Summary: The authors develop MAPKi sensitivity scores (MSS) to predict response to MAPKi in pediatric low-grade gliomas (pLGG) and validate their effectiveness using bulk and single-cell sequencing datasets. The MSSs successfully distinguish sensitive and non-sensitive cells and correlate with treatment response in independent datasets. These MSSs are important for patient stratification and should be validated in clinical trials.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Manuel Lauinger, Daniel Christen, Rhena F. U. Klar, Carole Roubaty, Christoph E. Heilig, Michael Stumpe, Jennifer J. Knox, Nikolina Radulovich, Laura Tamblyn, Irene Y. Xie, Peter Horak, Andrea Forschner, Michael Bitzer, Uwe A. Wittel, Melanie Boerries, Claudia R. Ball, Christoph Heining, Hanno Glimm, Martina Froehlich, Daniel Huebschmann, Steven Gallinger, Ralph Fritsch, Stefan Froehling, Grainne M. O'Kane, Joern Dengjel, Tilman Brummer
Summary: This study functionally characterizes BRAF exon 12 deletions and compares them with other BRAF ss 3-alpha C mutants. It demonstrates that BRAF(Delta ss 3-alpha C) deletion mutants form stable dimers and multiprotein complexes, and their dimerization is necessary. Some mutants with aromatic amino acid insertions at the deletion junction exhibit resistance to monomer-favoring RAF inhibitors while being sensitive to dimer-favoring inhibitors.
Meeting Abstract
Oncology
Romain Sigaud, Lisa Roesch, Charlotte Gatzweiler, Julia Benzel, Laura von Soosten, Heike Peterziel, Sara Najafi, Simay Ayhan, Xena F. Gerloff, Nina Hofmann, Isabel Buedenbender, Kathrin I. Foerster, Juergen Burhenne, Remi Longuespee, Cornelis M. van Tilburg, David T. W. Jones, Stefan M. Pfister, Deborah Knoerzer, Brent Kreider, Max Sauter, Kristian W. Pajtler, Marc Zuckermann, Ina Oehme, Olaf Witt, Till Milde
Meeting Abstract
Oncology
Romain Sigaud, Anja Stefanski, Florian Selt, Thomas Hielscher, Diren Usta, Daniela Kocher, Daniel Picard, Isabel Buedenbender, Marc Remke, Stefan M. Pfister, David T. W. Jones, Tilman Brummer, Olaf Witt, Till Milde
Meeting Abstract
Oncology
Daniela Kocher, Florian Selt, Gintvile Valinciute, Julia Zaman, David Vonhoeren, Stefan Pusch, Romain Guiho, Juan Pedro Martinez-Barbera, Andreas von Deimling, Stefan M. Pfister, David T. W. Jones, Tilman Brummer, Olaf Witt, Till Milde, Romain Sigaud
Article
Medicine, Research & Experimental
Lena Hoelzen, Jan Mitschke, Claudia Schoenichen, Maria Elena Hess, Sophia Ehrenfeld, Melanie Boerries, Cornelius Miething, Tilman Brummer, Thomas Reinheckel
Summary: This study suggests that proteases can act synergistically with PI3K inhibition in breast cancer cells, leading to enhanced therapeutic outcomes. Through a series of experiments, the researchers identified Usp7, Metap1, and Metap2 as key proteases that exhibit synthetic lethal effects when combined with PI3K inhibitors.
