Article
Oncology
Christos Adamopoulos, Tamer A. Ahmed, Maxwell R. Tucker, Peter M. U. Ung, Min Xiao, Zoi Karoulia, Angelo Amabile, Xuewei Wu, Stuart A. Aaronson, Celina Ang, Vito W. Rebecca, Brian D. Brown, Avner Schlessinger, Meenhard Herlyn, Qi Wang, David E. Shaw, Poulikos Poulikakos
Summary: A new class of RAF inhibitors that selectively target dBRAF over mBRAF has been identified and the basis of their selectivity has been determined. A rationally designed combination of RAF and MEK inhibitors based on their conformation selectivity achieved increased efficacy and a high therapeutic index when used to target BRAF(V600E) tumors.
Article
Cell Biology
Hui Li, Bingxin Guan, Sen Liu, Haiting Liu, Lin Song, Guohao Zhang, Ruinan Zhao, Chengjun Zhou, Peng Gao
Summary: Gastric cancer is a highly heterogeneous disease with poor prognosis. Protein tyrosine phosphatases, specifically PTPN14, play a vital role in gastric cancer by promoting cell proliferation, migration, and invasion.
CELL DEATH & DISEASE
(2023)
Article
Biochemistry & Molecular Biology
Caixia Hou, Abhisek Mandal, Juergen Rohr, Oleg Tsodikov
Summary: The ETS family transcription factors ERG and FLI1 play a key role in oncogenesis of prostate cancer and Ewing sarcoma, while MTM functions as an effective antagonist of ERG and FLI1. Studies of crystal structures and DNA binding reveal the disruption mechanism of MTM analogues on the interaction of ERG and FLI1.
Article
Cell Biology
Xiangpeng Dai, Xiaoling Zhang, Qing Yin, Jia Hu, Jianping Guo, Yang Gao, Aidan H. Snell, Hiroyuki Inuzuka, Lixin Wan, Wenyi Wei
Summary: This study reveals that the acetyltransferase p300 activates BRAF kinase by promoting BRAF K601 acetylation, which plays a significant role in melanoma and is associated with resistance to BRAF(V600E) inhibitors.
Article
Multidisciplinary Sciences
Evgeny Shlevkov, Paramasivam Murugan, Dan Montagna, Eric Stefan, Adelajda Hadzipasic, James S. Harvey, P. Rajesh Kumar, Sonya Entova, Nupur Bansal, Shari Bickford, Lai-Yee Wong, Warren D. Hirst, Andreas Weihofen, Laura F. Silvian
Summary: Compounds were identified that enhance the activity of Parkin, but they have limited effectiveness in a cellular context.
Article
Biochemistry & Molecular Biology
Jui-Hung H. Weng, Phillip T. Aoto, Robin Lorenz, Jian Wu, Sven Schmidt, Jascha Manschwetus, Pallavi Kaila-Sharma, Steve W. Silletti, Sebastian S. Mathea, Deep Chatterjee, Stefan Knapp, Friedrich Herberg, Susan Taylor
Summary: This study generated a comprehensive dynamic allosteric portrait of the C-terminal domains of LRRK2 using HDX-MS and MD simulations. It identified two helices that regulate LRRK2 conformation and function, providing potential sites for pharmacological intervention.
Article
Multidisciplinary Sciences
Keshav Patil, Earl Joseph Jordan, Jin H. Park, Krishna Suresh, Courtney M. Smith, Abigail A. Lemmon, Yael P. Mosse, Mark A. Lemmon, Ravi Radhakrishnan
Summary: Kinases are crucial in various cellular processes and commonly mutated in cancer, their activation status can be effectively predicted through computational studies despite mutations occurring throughout the kinase domain. The results provide insights into convergent activation mechanisms in majority of studied mutations.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Qing-Lan Li, Xiang Lin, Ya-Li Yu, Lin Chen, Qi-Xin Hu, Meng Chen, Nan Cao, Chen Zhao, Chen-Yu Wang, Cheng-Wei Huang, Lian-Yun Li, Mei Ye, Min Wu
Summary: This study analyzed active enhancers in colorectal cancer patients using genomics, transcriptomics, and epigenomics, identifying variant super-enhancer loci and KLF3 as a relevant transcription factor. The research provides important epigenomic resource and functional factors for epigenetic studies in colorectal cancer, shedding light on the role of super enhancers in regulating colorectal cancer tumorigenesis. Multiple key transcription factors in colorectal cancer were predicted with motif analysis and core regulatory circuitry analysis.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
April Lo, Kristin Holmes, Shriya Kamlapurkar, Filip Mundt, Sitapriya Moorthi, Iris Fung, Shaunt Fereshetian, Jacqueline Watson, Steven A. Carr, Philipp Mertins, Alice H. Berger
Summary: Mutant KRAS and RIT1 were found to promote canonical RAS signaling, while overexpression of wild-type RIT1 partially phenocopied oncogenic RIT1 and KRAS, inducing epithelial-to-mesenchymal transition. The study suggests that RIT1 protein abundance plays a role in its pathogenic function, and chromosomal amplification of wild-type RIT1 in lung and other cancers may be tumorigenic.
Editorial Material
Oncology
Bart Vanhaesebroeck, John E. Burke, Ralitsa R. Madsen
Summary: PIK3CA is a frequently activated kinase gene in solid tumors. This study shows that the PI3Kα inhibitors taselisib and inavolisib can induce degradation of mutant p110α protein in breast cancer cells that are positive for HER2 RTK, thereby limiting feedback-mediated drug resistance and potentially widening the therapeutic range of PI3Kα inhibition.
Article
Biochemistry & Molecular Biology
Kaavya Krishna Kumar, Evan S. O'Brien, Chris H. Habrian, Naomi R. Latorraca, Haoqing Wang, Inga Tuneew, Elizabeth Montabana, Susan Marqusee, Daniel Hilger, Ehud Y. Isacoff, Jesper Mosolff Mathiesen, Brian K. Kobilka
Summary: RAMP2 directly interacts with the glucagon receptor (GCGR) and inhibits downstream signaling. It enhances flexibility in specific regions, leading to the inhibition of active and intermediate states of the receptor. Cryo-EM structure analysis reveals that RAMP2 enhances conformational sampling of the receptor extracellular domain (ECD) and acts as a negative allosteric modulator of GCGR.
Article
Multidisciplinary Sciences
Andrew D. Weems, Erik S. Welf, Meghan K. Driscoll, Felix Y. Zhou, Hanieh Mazloom-Farsibaf, Bo-Jui Chang, Vasanth S. Murali, Gabriel M. Gihana, Byron G. Weiss, Joseph Chi, Divya Rajendran, Kevin M. Dean, Reto Fiolka, Gaudenz Danuser
Summary: Most human cells require anchorage for survival, and loss of cell-substrate adhesion can result in anoikis, a form of programmed cell death. Blebbing, the formation of small hemispherical plasma membrane protrusions, triggers the formation of signalling hubs that confer anoikis resistance by recruiting septin proteins as scaffolds for mutant NRAS and effectors. These signalling hubs activate pro-survival pathways, such as ERK and PI3K. Inhibition of blebs or septins in detached cells causes mislocalization of NRAS, reduced MAPK and PI3K activity, and cell death. Therefore, blebs play a crucial role in providing robust anoikis resistance.
Article
Chemistry, Multidisciplinary
Elaine C. Petronilho, Murilo M. Pedrote, Mayra A. Marques, Yulli M. Passos, Michelle F. Mota, Benjamin Jakobus, Gileno dos Santos de Sousa, Filipe Pereira da Costa, Adriani L. Felix, Giulia D. S. Ferretti, Fernando P. Almeida, Yraima Cordeiro, Tuane C. R. G. Vieira, Guilherme A. P. de Oliveira, Jerson L. Silva
Summary: Mutant p53 tends to form aggregates with amyloid properties, especially amyloid oligomers inside the nucleus, which are believed to cause oncogenic gain-of-function. The DNA-binding domain of p53 (p53C) undergoes phase separation and aggregation in the presence of polyethylene glycol (PEG), and mutant p53C undergoes phase separation faster than wild-type p53C. Mutant p53 undergoes gel- and solid-like phase transitions in the nucleus, modulated by polyanions like heparin and RNA. The disordered transactivation domain (TAD) also plays a role in phase separation and amyloid aggregation of p53.
Article
Medicine, Research & Experimental
Noriko Makita, Junichiro Sato, Katsunori Manaka, Kimiko Akahane, Takahiro Ito, Hajime Yamazaki, Akira Mizoguchi, Yusuke Hikima, Hirofumi Horikoshi, Masaomi Nangaku, Taroh Iiri
Summary: Observations on patients with AHH have revealed common characteristics that may provide new insights into the phenotype and characteristics of AHH, as well as the mechanisms by which biased agonism of GPCRs operates.
Article
Chemistry, Medicinal
Sara Bobone, Luca Pannone, Barbara Biondi, Maja Solman, Elisabetta Flex, Viviana Claudia Canale, Paolo Calligari, Chiara De Faveri, Tommaso Gandini, Andrea Quercioli, Giuseppe Torini, Martina Venditti, Antonella Lauri, Giulia Fasano, Jelmer Hoeksma, Valerio Santucci, Giada Cattani, Alessio Bocedi, Giovanna Carpentieri, Valentina Tirelli, Massimo Sanchez, Cristina Peggion, Fernando Formaggio, Jeroen den Hertog, Simone Martinelli, Gianfranco Bocchinfuso, Marco Tartaglia, Lorenzo Stella
Summary: A new class of inhibitors targeting protein-protein interactions of the SHP2 phosphatase were developed, showing potential for cancer and rare disease therapy. These inhibitors exhibit high affinity and selectivity, with stronger affinity for pathogenic SHP2 mutants. The best peptide inhibitor demonstrated promising effects in zebrafish embryos, indicating a novel route for SHP2-targeted therapies and further research into protein-protein interactions in SHP2 function.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Editorial Material
Oncology
Bart Vanhaesebroeck, John E. Burke, Ralitsa R. Madsen
Summary: PIK3CA is a frequently activated kinase gene in solid tumors. This study shows that the PI3Kα inhibitors taselisib and inavolisib can induce degradation of mutant p110α protein in breast cancer cells that are positive for HER2 RTK, thereby limiting feedback-mediated drug resistance and potentially widening the therapeutic range of PI3Kα inhibition.
Article
Chemistry, Multidisciplinary
Chiara Borsari, Erhan Keles, Jacob A. McPhail, Alexander Schaefer, Rohitha Sriramaratnam, Wojciech Goch, Thorsten Schaefer, Martina De Pascale, Wojciech Bal, Matthias Gstaiger, John E. Burke, Matthias P. Wymann
Summary: This study demonstrates a design strategy for covalent protein kinase inhibitors targeting PI3Kα by introducing reactive warheads. Compounds with high inhibitory activity and long-lasting efficacy have been identified.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Review
Cell Biology
Jacob A. McPhail, John E. Burke
Summary: Lipid phosphoinositides play important roles as signaling molecules and markers of organelle identity in eukaryotic cells. Viruses can manipulate the kinases and phosphatases involved in phosphoinositide generation for their replication. This review focuses on PI4KA and PI4KB, discussing their roles in signaling, membrane trafficking, and virus manipulation. The molecular mechanisms by which PI4KA and PI4KB are activated and usurped by viruses are also explored.
Article
Multidisciplinary Sciences
Aleksandra Levina, Kaelin D. Fleming, John E. Burke, Thomas A. Leonard
Summary: This study elucidates the mechanism of self-activation of 3-phosphoinositide-dependent kinase 1 (PDK1). It is activated by dimerization mediated by PIP3 and trans-autophosphorylation, while its PH domain inhibits its activity. These results suggest that phosphoinositide-dependent activation may also apply to various effector kinases.
NATURE COMMUNICATIONS
(2022)
Article
Biology
Edhriz Siraliev-Perez, Jordan T. B. Stariha, Reece M. Hoffmann, Brenda R. S. Temple, Qisheng Zhang, Nicole Hajicek, Meredith L. Jenkins, John E. Burke, John Sondek
Summary: It has been discovered that PLC-gamma 1 is relatively inert to lipid vesicles containing its substrate, PIP2, unless it is bound to the kinase domain of FGFR1. The binding of FGFR1 activates PLC-gamma 1 and leads to its priming. This priming process is expected to be enhanced for receptors embedded in membranes and may involve cooperativity between receptor engagement and membrane proximity.
Article
Biochemistry & Molecular Biology
Brendon J. Medley, Leif Leclaire, Nicole Thompson, Keira E. Mahoney, Benjamin Pluvinage, Matthew A. H. Parson, John E. Burke, Stacy Malaker, Warren Wakarchuk, Alisdair B. Boraston
Summary: Akkermansia muciniphila, a key member of the human gut microbiota, has a significant impact on host health through its interaction with host mucin. This study identifies an uncharacterized protein, AMUC_1438, as a unique O-glycopeptidase with mucin-degrading capacity. The protein has a metzincin metalloprotease catalytic motif and specifically recognizes a GalNAc residue alpha-linked to serine or threonine. This understanding of the protein's structure and function contributes to the broader understanding of O-glycopeptidase enzymes and their role in host adaptation.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Udit Dalwadi, Elaina Corrado, Kaelin D. Fleming, Brandon E. Moeller, Sung-Eun Nam, John E. Burke, Calvin K. Yip
Summary: Trimer Independent of NuA4 involved in Transcription Interactions with Nucleosomes (TINTIN) is an integral module of the NuA4 complex in yeast, playing crucial roles in transcription regulation and DNA repair. This study provides insights into the dynamics of TINTIN and the regulation of its interactions with chromatin.
MOLECULAR AND CELLULAR BIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Matthew A. H. Parson, Meredith L. Jenkins, John E. Burke
Summary: This review discusses the application of Hydrogen-deuterium exchange mass spectrometry (HDX-MS) as a powerful biophysical tool for studying the structure and function of intrinsically disordered regions in proteins. The focus is on the theory of hydrogen exchange and its practical application in identifying disordered regions and characterizing their involvement in protein-protein and protein-membrane interfaces.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2022)
Review
Biotechnology & Applied Microbiology
John E. Burke, Joanna Triscott, Brooke M. Emerling, Gerald R. Hammond
Summary: This Review describes the structure, function, regulation, and disease roles of clinically relevant PIKs outside of class I PI3Ks, as well as the development of potent and specific small-molecule inhibitors. Phosphoinositide kinases are master regulators of cellular processes and their dysregulation has been implicated in various human diseases. Recent years have seen increased interest in targeting phosphoinositide kinases beyond class I PI3Ks, leading to the clinical development of selective inhibitors. This comprehensive analysis provides an overview of the current understanding and progress in the development of phosphoinositide kinase inhibitors.
NATURE REVIEWS DRUG DISCOVERY
(2023)
Article
Multidisciplinary Sciences
Ronja Reinhardt, Kai Hirzel, Gisela Link, Stephan A. Eisler, Tanja Hagele, Matthew A. H. Parson, John E. Burke, Angelika Hausser, Thomas A. Leonard
Summary: Phosphorylation is a common mechanism in cell signaling, and protein kinases are often regulated by phosphorylation. However, PKD regulates itself through dimerization-mediated trans-autoinhibition, followed by autophosphorylation, to control its activity.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Meredith L. Jenkins, Harish Ranga-Prasad, Matthew A. H. Parson, Noah J. Harris, Manoj K. Rathinaswamy, John E. Burke
Summary: The PIK3CA gene is frequently mutated in human cancer, and this study reveals the molecular mechanisms underlying the increased activity mediated by different oncogenic mutations in PIK3CA. Through a combination of biochemical assays and HDX-MS, the authors uncover unique regulatory mechanisms and explain how these mutations activate PI3K. This work has important implications for the development of mutant selective inhibitors.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Alexandria L. Shaw, Matthew A. H. Parson, Linda Truebestein, Meredith L. Jenkins, Thomas A. Leonard, John E. Burke
Summary: Akt is a key regulator of cell growth signaling and its hyperactivation is oncogenic. This study used hydrogen deuterium exchange mass spectrometry to investigate the conformational changes induced by Akt inhibitors. The findings provide valuable insights for designing targeted therapeutics against Akt.
Article
Cell Biology
Manoj K. Rathinaswamy, Meredith L. Jenkins, Benjamin R. Duewell, Xuxiao Zhang, Noah J. Harris, John T. Evans, Jordan T. B. Stariha, Udit Dalwadi, Kaelin D. Fleming, Harish Ranga-Prasad, Calvin K. Yip, Roger L. Williams, Scott D. Hansen, John E. Burke
Summary: This study investigates the activation mechanisms of phosphoinositide 3-kinase (PI3Ky) in immune cells. Using various experimental methods, the researchers identified molecular differences between the p110y-p84 and p110y-p101 complexes, which explain their differential membrane recruitment and activation by Ras and GPCRs. The findings provide key insights into the molecular basis of PI3Ky complex activation.
Article
Multidisciplinary Sciences
Anna C. Howes, Olga Perisic, Roger L. Williams
Summary: This study determined the structure of H2O2-activated ATM using cryo-EM, revealing the structural remodeling and active site optimization that occur during oxidative activation of ATM. The captured substrate binding also provides insights into the mechanism of ATM activation during oxidative stress.
