Article
Biochemical Research Methods
Turkan Haliloglu, Aysima Hacisuleyman, Burak Erman
Summary: In this article, a computational model is presented to predict the paths of maximum information transfer between active and allosteric sites in proteins by using mutual information as the measure. The model is tested on six widely studied cases and the results correlate well with experimental data. The model provides crucial information for understanding and controlling protein functionality.
Article
Multidisciplinary Sciences
Kyle K. Nishikawa, Nicholas Hoppe, Robert Smith, Craig Bingman, Srivatsan Raman
Summary: Epistasis is a crucial factor in the emergence of novel protein function, particularly in allosteric proteins. By combining functional, structural, and biophysical analyses, researchers have demonstrated the significant impact of epistasis on biological function and structure in mutant proteins.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Physical
Juan Xie, Gaoxiang Pan, Yibo Li, Luhua Lai
Summary: This study demonstrates the importance of protein topology in allosteric regulation, showing that allosteric proteins mainly have multiple domains or subunits, and allosteric sites are often located between domains of the same fold type. A novel method, called TopoAlloSite, was developed to predict the location of allosteric sites on protein topology, successfully identifying cryptic allosteric sites in several proteins. This research provides insights for finding new druggable targets and designing allosteric drugs.
JOURNAL OF CHEMICAL PHYSICS
(2023)
Article
Biochemistry & Molecular Biology
Mai Luo, Jessica N. Spradlin, Lydia Boike, Bingqi Tong, Scott M. Brittain, Jeffrey M. McKenna, John A. Tallarico, Markus Schirle, Thomas J. Maimone, Daniel K. Nomura
Summary: This study found that the natural product nimbolide can be used as a recruiter of the E3 ubiquitin ligase RNF114 for targeted protein degradation, which is important in modern drug discovery. Through activity-based protein profiling-enabled ligand screening, fully synthetic molecules mimicking nimbolide were discovered, showing potential for degrading therapeutic targets.
CELL CHEMICAL BIOLOGY
(2021)
Article
Cell Biology
Yi Fu, Yaqian Huang, Zhao Yang, Yufei Chen, Jingang Zheng, Chenfeng Mao, Zhiqing Li, Zhixin Liu, Bing Yu, Tuoyi Li, Meili Wang, Chanjuan Xu, Yiwei Zhou, Guizhen Zhao, Yiting Jia, Wei Guo, Xin Jia, Tao Zhang, Li Li, Ziyi Liu, Shengchao Guo, Mingliang Ma, Heng Zhang, Bo Liu, Junbao Du, Wengong Wang, Chaoshu Tang, Pei Gao, Qingbo Xu, Xian Wang, Jianfeng Liu, Jinpeng Sun, Wei Kong
Summary: This study reveals that the extracellular matrix protein COMP acts as an endogenous allosteric biased modulator of the AT1 receptor, inhibiting specific signaling pathways through the regulation of intracellular conformational states. COMP deficiency leads to exclusive AAA formation in response to AngII infusion, indicating a potential therapeutic target for cardiovascular diseases.
Article
Biochemistry & Molecular Biology
Binfen Chen, Xinmei Yu, Ting Gao, Yaoyao Wu, Xiaojun Zhang, Sanshu Li
Summary: Aptamers are RNA or DNA molecules that can bind to ligands and have various applications such as biosensors, diagnostic tools, and therapeutic agents. The traditional method of selecting aptamers and integrating an expression platform has limitations, but this study introduces the use of allosteric DNAzymes known as aptazymes to overcome these drawbacks. The researchers used the Expression-SELEX technique to select aptazymes specifically activated by low concentrations of l-phenylalanine. Three aptazymes were characterized and found to have a high affinity for l-phenylalanine, improved catalytic rate in its presence, and the ability to discriminate against similar analogs. This work demonstrates the effectiveness of Expression-SELEX in enriching high-quality ligand-responsive aptazymes.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Chemistry, Multidisciplinary
Adele Hardie, Benjamin P. Cossins, Silvia Lovera, Julien Michel
Summary: We propose a workflow using Markov State Models (MSMs) with steered molecular dynamics (sMD) to assess the allosteric potential of known binders.
COMMUNICATIONS CHEMISTRY
(2023)
Article
Medicine, Research & Experimental
Adam P. Curnock, Giovanna Bossi, Jyothi Kumaran, Lindsay J. Bawden, Rita Figueiredo, Rajeevkumar Tawar, Katherine Wiseman, Emma Henderson, Sec Julie Hoong, Veronica Gonzalez, Hemza Ghadbane, David Eo Knight, Ronan O'Dwyer, David X. Overton, Christina M. Lucato, Nicola Mg Smith, Carlos R. Reis, Keith Page, Lorraine M. Whaley, Michelle L. McCully, Stephen Hearty, Tara M. Mahon, Peter Weber
Summary: The study developed PD-1 agonist ImmTAAI molecules that can inhibit T cell function by mimicking the action of PD-L1. These molecules specifically bind to target cells and effectively activate the PD-1 receptor on interacting T cells, achieving immune suppression.
Article
Multidisciplinary Sciences
Xinyu Xu, Jeremy Shonberg, Jonas Kaindl, Mary J. J. Clark, Anne Stoessel, Luis Maul, Daniel Mayer, Harald Huebner, Kunio Hirata, A. J. Venkatakrishnan, Ron O. O. Dror, Brian K. K. Kobilka, Roger K. K. Sunahara, Xiangyu Liu, Peter Gmeiner
Summary: Constrained catecholamines exhibit high selectivity for the beta(2)AR due to reduced ligand flexibility and a less stable binding pocket in the beta(1)AR. Surrounding residues in the extracellular loops (ECLs) of the receptors allosterically modify the binding pocket, resulting in different affinity and selectivity for the beta(2)AR. Exploiting these allosteric influences may lead to the development of more subtype-selective GPCR ligands.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Marjorie Damian, Maxime Louet, Antoniel Augusto Severo Gomes, Celine M'Kadmi, Severine Denoyelle, Sonia Cantel, Sophie Mary, Paulo M. Bisch, Jean-Alain Fehrentz, Laurent J. Catoire, Nicolas Floquet, Jean-Louis Baneres
Summary: The membrane plays a crucial role in modulating the signaling efficacy and selectivity of the ghrelin receptor GHSR through specific lipid interactions and bulk effects. PIP2 and GM3 induce shifts in the conformational equilibrium of GHSR, favoring G protein activation in different ways.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Multidisciplinary
Matthew G. Alteen, Hayden Peacock, Richard W. Meek, Jil A. Busmann, Sha Zhu, Gideon J. Davies, Hiroaki Suga, David J. Vocadlo
Summary: This study applied an mRNA display technology with genetic code reprogramming to identify macrocyclic peptides that can inhibit O-GlcNAc transferase (OGT) activity. These macrocycles bind to the tetratricopeptide repeats of OGT and inhibit its activity through an allosteric mechanism. The high potency and novel mechanism of action of these OGT ligands may contribute to further understanding the specificity and regulation of OGT.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Physical
Kirill A. Konovalov, Cheng-Guo Wu, Yunrui Qiu, Vijaya Kumar Balakrishnan, Pankaj Singh Parihar, Michael S. O'Connor, Yongna Xing, Xuhui Huang
Summary: Mutations in protein phosphatase 2A (PP2A) disrupt its autoinhibition and phosphorylation-induced activation, leading to intellectual disability and cancer. Allosteric pathway analysis and biochemical experiments reveal that the disease mutant E198K weakens the stabilizing pathways of the regulatory subunit B56d, while the mutant E200K induces exposure of the active site. Remarkably, the allosteric pathways of E198K resemble those in phosphorylation-activated WT, suggesting a conserved mechanism for alleviating autoinhibition.
JOURNAL OF CHEMICAL PHYSICS
(2023)
Article
Biochemistry & Molecular Biology
Michal Gala, Peter Pristas, Gabriel Zoldak
Summary: This paper examined the impact of opening and formation of subdomain interfaces during the evolution of Heat shock proteins 70 (Hsp70). It found that indel events, such as insertions and deletions, in specific regions disrupt the mechanical balance of the protein and cause dysfunction. The study highlights the importance of considering the balance between structural elements in the rational design of functional allosteric machines.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Neurosciences
Kiran Sapkota, Erica S. Burnell, Mark W. Irvine, Guangyu Fang, Dinesh Y. Gawande, Shashank M. Dravid, David E. Jane, Daniel T. Monaghan
Summary: The study characterizes a novel NMDAR antagonist, UBP792, which displays partial subtype-selectivity and inhibits NMDAR responses by reducing the potency and efficacy of L-glutamate and glycine. It acts non-competitively, with activity independent of voltage and affected by pH, and potentially stabilizes different channel conformations to inhibit NMDAR function. This expands the possibilities for developing NMDAR modulators with appropriate selectivity for therapeutic indications.
Article
Biology
Atilio Reyes Romero, Serjey Lunev, Grzegorz M. Popowicz, Vito Calderone, Matteo Gentili, Michael Sattler, Jacek Plewka, Michal Taube, Maciej Kozak, Tad A. Holak, Alexander S. S. Domling, Matthew R. Groves
Summary: Romero et al. conducted NMR-based screening of 1500 fragments to identify those binding at the oligomeric interface of malate dehydrogenase (MDH). Their study indicates an allosteric mechanism affecting enzymatic activity, paving the way for development of more selective molecules and serving as a starting point for future specific MDH inhibitor development.
COMMUNICATIONS BIOLOGY
(2021)
Article
Biotechnology & Applied Microbiology
Emma Dann, Neil C. Henderson, Sarah A. Teichmann, Michael D. Morgan, John C. Marioni
Summary: Milo is a scalable statistical framework that performs differential abundance testing by assigning cells to partially overlapping neighborhoods on a k-nearest neighbor graph. It can identify perturbations obscured by discretizing cells into clusters and outperforms alternative testing strategies. Milo is based on cell-cell similarity structure and may be applicable to various single-cell data beyond scRNA-seq.
NATURE BIOTECHNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Mihaly Varadi, Stephen Anyango, David Armstrong, John Berrisford, Preeti Choudhary, Mandar Deshpande, Nurul Nadzirin, Sreenath S. Nair, Lukas Pravda, Ahsan Tanweer, Bissan Al-Lazikani, Claudia Andreini, Geoffrey J. Barton, David Bednar, Karel Berka, Tom Blundell, Kelly P. Brock, Jose Maria Carazo, Jiri Damborsky, Alessia David, Sucharita Dey, Roland Dunbrack, Juan Fernandez Recio, Franca Fraternali, Toby Gibson, Manuela Helmer-Citterich, David Hoksza, Thomas Hopf, David Jakubec, Natarajan Kannan, Radoslav Krivak, Manjeet Kumar, Emmanuel D. Levy, Nir London, Jose Ramon Macias, Madhusudhan M. Srivatsan, Debora S. Marks, Lennart Martens, Stuart A. McGowan, Jake E. McGreig, Vivek Modi, R. Gonzalo Parra, Gerardo Pepe, Damiano Piovesan, Jaime Prilusky, Valeria Putignano, Leandro G. Radusky, Pathmanaban Ramasamy, Atilio O. Rausch, Nathalie Reuter, Luis A. Rodriguez, Nathan J. Rollins, Antonio Rosato, Luis Serrano, Gulzar Singh, Petr Skoda, Carlos Oscar S. Sorzano, Jan Stourac, Joanna Sulkowska, Radka Svobodova, Natalia Tichshenko, Silvio C. E. Tosatto, Wim Vranken, Mark N. Wass, Dandan Xue, Daniel Zaidman, Janet Thornton, Michael Sternberg, Christine Orengo, Sameer Velankar
Summary: PDBe-KB is an open collaboration platform that aims to integrate functional and biophysical annotations from world-leading specialist data resources, serving the Protein Data Bank. By developing standardized data exchange formats and integrating functional annotations from partner resources, PDBe-KB aims to place macromolecular structure data in a biological context and provide valuable biological insights.
NUCLEIC ACIDS RESEARCH
(2022)
Review
Genetics & Heredity
Rasa Elmentaite, Cecilia Dominguez Conde, Lu Yang, Sarah A. Teichmann
Summary: The development of single-cell and spatial transcriptomics methods has enabled the conception of the Human Cell Atlas initiative, aiming to generate an integrated map of all cells in the human body. By studying human tissues using single-cell gene expression data, we are gaining insights into the commonalities and tissue-specific features of major and supportive cell types within human organs.
NATURE REVIEWS GENETICS
(2022)
Article
Multidisciplinary Sciences
Stanislau Yatskevich, Kyle W. Muir, Dom Bellini, Ziguo Zhang, Jing Yang, Thomas Tischer, Masa Predin, Tom Dendooven, Stephen H. McLaughlin, David Barford
Summary: This study reveals that CCAN can bind to CENP-A(Nuc) and form a robust structure around the linker DNA, enabling kinetochores to withstand forces exerted by the mitotic spindle.
Article
Multidisciplinary Sciences
Jarrod Shilts, Yannik Severin, Francis Galaway, Nicole Mueller-Sienerth, Zheng-Shan Chong, Sophie Pritchard, Sarah Teichmann, Roser Vento-Tormo, Berend Snijder, Gavin J. Wright
Summary: In this study, we systematically mapped the direct protein interactions across a recombinant library that includes most of the surface proteins on human leukocytes, providing a high-confidence and quantitative view of the receptor wiring that connects human immune cells. By integrating our interactome with expression data, we identified trends in the dynamics of immune interactions and constructed a mathematical model that predicts cellular connectivity. We also developed an interactive multi-tissue single-cell atlas to infer immune interactions throughout the body and linked our receptor interactions to functional roles through protein stimulation and microscopy.
Editorial Material
Multidisciplinary Sciences
Sarah A. Teichmann, Muzlifah Haniffa, Jasmin Fisher
Summary: Diversity is a creative force that broadens views and enhances ideas, increasing productivity and the impact of science. Every research organization, whether in academia or industry, needs better inclusion policies to harness the benefits of diversity. We share our suggestions on promoting inclusion in academia and creating a better research culture for all, drawing from our experiences as women in science.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Tamara Sijacki, Pablo Alcon, Zhuo A. Chen, Stephen H. McLaughlin, Shabih Shakeel, Juri Rappsilber, Lori A. Passmore
Summary: This study reveals that phosphorylation of FANCI by the ATR DNA damage kinase primes the FANCD2-FANCI clamp for ubiquitination, facilitating the initiation of DNA cross-link repair.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Elyse S. Fischer, Conny W. H. Yu, Johannes F. Hevler, Stephen H. McLaughlin, Sarah L. Maslen, Albert J. R. Heck, Stefan M. Freund, David Barford
Summary: This study reveals the complex interaction network required for the formation of the MCC during mitosis. The assembly of MCC is initiated by Mad1 on unattached kinetochores and facilitated by a phosphorylation-dependent scaffold for the binding of Cdc20 and Mad2. This research is of great importance for a better understanding of the regulatory mechanisms of cell division.
NATURE COMMUNICATIONS
(2022)
Article
Microbiology
Tim Nierhaus, Stephen H. McLaughlin, Frank Burmann, Danguole Kureisaite-Ciziene, Sarah L. Maslen, J. Mark Skehel, Conny W. H. Yu, Stefan M. Freund, Louise F. H. Funke, Jason W. Chin, Jan Lowe
Summary: FtsA and FtsN form double filaments to regulate peptidoglycan synthesis during bacterial cell division; FtsZ forms the Z-ring as a cytoplasmic scaffold; FtsA anchors the Z-ring to the membrane.
NATURE MICROBIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Jennifer E. Rood, Aidan Maartens, Anna Hupalowska, Sarah A. Teichmann, Aviv Regev
Summary: Single-cell atlases have the potential to bridge the gap between genes, diseases, and therapies. By understanding disease mechanisms at the cellular and tissue levels, they can aid in disease diagnostics, drug target identification, and the development of new therapies.
Review
Cardiac & Cardiovascular Systems
Antonio M. A. Miranda, Vaibhao Janbandhu, Henrike Maatz, Kazumasa Kanemaru, James Cranley, Sarah A. Teichmann, Norbert Huebner, Michael D. Schneider, Richard P. Harvey, Michela Noseda
Summary: Cardiovascular disease is the leading cause of death globally. Understanding its mechanisms through advanced single-cell and single-nucleus transcriptomics studies is crucial for improving therapeutic strategies and patient risk assessment. This review provides an overview of the challenges and inferences in experimental design, as well as novel findings and applications in cardiac cell types and states. It also discusses the need for standardization and the translational and clinical implications of these technologies in diagnosing and treating heart disease.
NATURE REVIEWS CARDIOLOGY
(2023)
Article
Biotechnology & Applied Microbiology
Hannah K. Neikes, Katarzyna W. Kliza, Cathrin Grawe, Roelof A. Wester, Pascal W. T. C. Jansen, Lieke A. Lamers, Marijke P. Baltissen, Simon J. van Heeringen, Colin Logie, Sarah A. Teichmann, Rik G. H. Lindeboom, Michiel Vermeulen
Summary: BANC-seq is a method to determine the absolute binding affinities of transcription factors to native DNA across the genome. It adds a quantitative dimension to transcription factor biology and allows prediction of binding sites under non-physiological conditions.
NATURE BIOTECHNOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Peerapat Khamwachirapithak, David Guillaume-Schoepfer, Pakkanan Chansongkrow, Sarah A. Teichmann, Philip A. Wigge, Varodom Charoensawan
Summary: This study combines ChIP-seq and RNA-seq to investigate the effects of global and local H3 depletion on gene transcription, as well as the interaction between the transcription factor Rap1 and H3. The results provide a working model and testable hypotheses regarding the impact of H3 depletion on transcriptional changes.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Article
Genetics & Heredity
Emma Dann, Ana-Maria Cujba, Amanda J. Oliver, Kerstin B. Meyer, Sarah A. Teichmann, John C. Marioni
Summary: Joint analysis of diseased tissues and healthy reference data can reveal altered cell states. Using a reference atlas for latent space learning followed by differential analysis against controls improves identification of disease-associated cells, especially with multiple perturbed cell types. Reducing control sample numbers does not increase false discovery rates.
Article
Multidisciplinary Sciences
Tom Dendooven, Ziguo Zhang, Jing Yang, Stephen H. McLaughlin, Johannes Schwab, Sjors H. W. Scheres, Stanislau Yatskevich, David Barford
Summary: The point centromere of budding yeast controls the assembly of large kinetochore complex for chromatid segregation. The kinetochore complex consists of the inner kinetochore (CCAN) and the outer kinetochore KNL1-MIS12-NDC80 (KMN) network. The cryo-electron microscopy structure reveals the assembly of the yeast inner kinetochore onto the centromere-specific CENP-A nucleosomes with unwrapped DNA ends. The CCAN protomers bind the free DNA duplexes and are connected through CBF3. A model is presented for the assembly of the inner kinetochore onto a point centromere and its organization of the outer kinetochore for chromosome attachment to the mitotic spindle.