Article
Chemistry, Medicinal
Rachel A. Powers, Cynthia M. June, Micah C. Fernando, Erin R. Fish, Olivia L. Maurer, Rachelle M. Baumann, Trevor J. Beardsley, Magdalena A. Taracila, Susan D. Rudin, Kristine M. Hujer, Andrea M. Hujer, Nicolo Santi, Valentina Villamil, Maria Luisa Introvigne, Fabio Prati, Emilia Caselli, Robert A. Bonomo, Bradley J. Wallar
Summary: Class C Acinetobacter-derived cephalosporinases (ADCs) are crucial targets for inhibition in multidrug-resistant Acinetobacter baumannii. Characterization of ADC variants and development of compounds that inhibit all prevalent ADCs are both important. The boronic acid transition state inhibitor, MB076, shows inhibitory activity against seven different ADC & beta;-lactamase variants.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Rong Li, Huilin Su, Wei Chen, Yu-Hang Yan, Cong Zhou, Luohe Mou, Huan Yang, Shan Qian, Zhouyu Wang, Lingling Yang, Guo-Bo Li
Summary: As an important mechanism of ss-lactam antimicrobial resistance, metallo-ss-lactamases (MBLs) have gained increasing attention worldwide. However, there is still a lack of clinically useful drugs to combat MBL-mediated resistance. In this study, 1H-imidazole-2-carboxylic acid was identified as a core metal-binding pharmacophore (MBP) to target multiple B1 MBLs, and further structural optimization led to the discovery of more potent MBL inhibitors.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Microbiology
Neha Baliyan, Kiran Dindhoria, Aman Kumar, Aman Thakur, Rakshak Kumar
Summary: This study investigated three substrate-based lugri for their biochemical properties and potential probiotics. Rice-based lugri was found to have higher alcohol content, electric conductivity, crude protein, and lower pH compared to barley and wheat-based lugri. A total of 43 probiotic strains were isolated, with rice-based undistilled lugri harboring the most probiotics. These bacterial isolates showed promising probiotic attributes and antioxidant activity, with Lacticaseibacillus paracasei LUL:01 identified as the best candidate for the production of fermented milk.
FRONTIERS IN MICROBIOLOGY
(2021)
Article
Microbiology
Bogdan M. Benin, Trae Hillyer, Aylin S. Crugnale, Andrew Fulk, Caitlyn A. Thomas, Michael W. Crowder, Matthew A. Smith, Woo Shik Shin
Summary: Multiple expression of beta-lactamases poses a threat to public health and patient mortality rates. Quercetin and its analogs show promise as potential metallo-beta-lactamase inhibitors.
Article
Nanoscience & Nanotechnology
Tadasha Jena, Md Tarik Hossain, Upasana Nath, Manabendra Sarma, Hiroshi Sugimoto, Minoru Fujii, P. K. Giri
Summary: In this study, it is discovered that intrinsic defects in 2D palladium diselenide (PdSe2) dendrites can serve as hotspots for high surface-enhanced Raman spectroscopy (SERS) enhancement. The vacancy-rich dendritic PdSe2 demonstrates a SERS enhancement factor >10(5) and can detect RhB at a concentration down to 10(-8) M. The topological defects and edge construction in PdSe2 dendrites contribute to the high enhancement in the SERS signal. This research bridges the gap between conventional plasmonic SERS substrates and plasmon-free SERS substrates.
NPJ 2D MATERIALS AND APPLICATIONS
(2023)
Article
Chemistry, Medicinal
Yuwen Jia, Barbara Schroeder, Yvonne Pfeifer, Christopher Froehlich, Lihua Deng, Christoph Arkona, Benno Kuropka, Jana Sticht, Kenichi Ataka, Silke Bergemann, Gerhard Wolber, Christoph Nitsche, Martin Mielke, Hanna-Kirsti S. Leiros, Guido Werner, Joerg Rademann
Summary: Carbapenem resistance caused by metallo-β-lactamases (MBLs) such as NDM-1 is a significant threat to the effectiveness of β-lactam antibiotics. In this study, 8-hydroxy- and 8-sulfonamido-quinoline-2-carboxylic acids were developed as potent inhibitors of NDM-1 with improved activity and binding affinity. These inhibitors formed reversible protein-inhibitor complexes with two zinc ions and showed remarkable entropic gain in NDM-1 structure. They effectively reduced the minimum inhibitory concentrations (MIC) of meropenem for multidrug-resistant bacteria expressing bla (NDM-1) and clinical strains without toxicity to human cells.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Mingyar N. Lopez-Hernandez, Jorge M. Vazquez-Ramos
Summary: Cyclin-dependent kinases (CDKs) play a critical role in controlling cell cycle progression by phosphorylating substrates. In animals, CDKs are activated by the association with cyclins and phosphorylation of a conserved threonine residue in the CDK activation loop. However, the mechanisms of CDKs activation and the relevance of cyclins for substrate targeting in plants have not been well studied.
Article
Biochemistry & Molecular Biology
Katarzyna Palica, Fritz Deufel, Susann Skagseth, Gabriela Paula Di Santo Metzler, Johannes Thoma, Anna Andersson Rasmussen, Arto Valkonen, Per Sunnerhagen, Hanna-Kirsti S. Leiros, Hanna Andersson, Mate Erdelyi
Summary: The upswing of antibiotic resistance, particularly resistance mediated by bacterial metallo-ss-lactamases, poses an escalating threat to human health. This study presents a series of novel non-cytotoxic alpha-aminophosphonate-based inhibitor candidates and investigates their inhibitory activities and binding modes. The findings suggest that phosphonate-type inhibitors may be potential therapeutic candidates for combating metallo-ss-lactamase resistant bacteria.
RSC MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Xiao Wang, Sanford M. Simon, Philip Coffino
Summary: This study used single molecule experiments to measure the dwell time of substrates interacting with the AAA+ ATPase unfoldase/translocase ClpX, finding that tail length and composition of the substrates affect substrate retention during futile unfolding. Both polyG and GAr have inhibitory effects on unfolding, but act differently.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Xiao Wang, Sanford M. Simon, Philip Coffino
Summary: In this study, the researchers investigated the effect of substrate sequence on the unfolding and degradation by the bacterial AAA+ ATPase unfoldase/translocase, ClpX. They found that the length and composition of the substrate tail can affect substrate retention and dissociation during futile unfolding. Additionally, they discovered that specific tail compositions, such as poly-glycine tracts and glycine-alanine repeats, can inhibit unfolding and degradation in different ways. Their findings highlight the importance of substrate characteristics in the unfolding and degradation process.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Cell Biology
Stephanie Patchett, Zongyang Lv, Wioletta Rut, Miklos Bekes, Marcin Drag, Shaun K. Olsen, Tony T. Huang
Summary: The study identified the S1 sensor region within the SARS-CoV-2 papain-like protease as a key determinant of substrate specificity. Variations in this region specifically alter cleavage of different substrates, which could potentially impact host antiviral immune responses to newly emerging SARS-CoV-2 lineages.
Article
Multidisciplinary Sciences
Ala M. Shaqra, Sarah N. Zvornicanin, Qiu Yu J. Huang, Gordon J. Lockbaum, Mark Knapp, Laura Tandeske, David T. Bakan, Julia Flynn, Daniel N. A. Bolon, Stephanie Moquin, Dustin Dovala, Nese Kurt Yilmaz, Celia A. Schiffer
Summary: The study determined the crystal structures of SARS-CoV-2 main protease (Mpro) bound to substrate peptides, defining the substrate envelope and identifying sites susceptible to drug resistance. These findings provide insights for developing robust inhibitors against SARS-CoV-2 and preventing drug resistance.
NATURE COMMUNICATIONS
(2022)
Article
Mathematics, Interdisciplinary Applications
Yu Gu, Muhammad Altaf Khan, Y. S. Hamed, Bassem F. Felemban
Summary: The study introduces a new mathematical model for analyzing COVID-19 infection using the Caputo derivative, explores stability and parameter estimation using real data, and provides numerical solutions that demonstrate the model's efficacy in describing disease interactions.
FRACTAL AND FRACTIONAL
(2021)
Review
Chemistry, Physical
Danish Khan, Geping Qu, Imran Muhammad, Zeguo Tang, Zong-Xiang Xu
Summary: This article provides an overview of the development of monolithic perovskite-silicon tandem solar cells and discusses the major challenges faced in achieving efficient, stable, and scalable devices. The relationship between perovskite band gap and silicon texture is crucial but currently unclear due to conflicting research outcomes.
ADVANCED ENERGY MATERIALS
(2023)
Article
Biophysics
Steven D. Walker, Adrian O. Olivares
Summary: The study reveals that ClpP can grip protein substrates under mechanical loads exceeding 40 pN, which is greater than those observed for other related proteases. The peptidase activity of ClpP does not affect the slip bond behavior and the unloaded bond lifetimes between ClpP and protein substrates are on a timescale relevant to unfolding times for difficult to unfold model substrate proteins.
BIOPHYSICAL JOURNAL
(2022)
Article
Biochemistry & Molecular Biology
Charlotte M. Miton, Karol Buda, Nobuhiko Tokuriki
Summary: Proteins are molecular machines made up of complex, highly connected amino acid networks, and their functional optimization requires the reorganization of these networks. Epistasis rewires intramolecular interactions to alter protein function, playing a crucial role in understanding evolutionary dynamics and sequence-structure-function relationships. Recent studies have provided insights into the molecular mechanisms of epistasis at the structural level, showcasing the intricate and fascinating nature of intramolecular networks co-opted during the evolution of protein function.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Dave W. Anderson, Florian Baier, Gloria Yang, Nobuhiko Tokuriki
Summary: This study characterizes the catalytic activity of a recently evolved bacterial enzyme under various laboratory conditions, revealing that adaptive landscapes may shift due to genotype-by-environment interactions and environment-dependent epistasis, impacting the fitness of functional mutations.
NATURE COMMUNICATIONS
(2021)
Article
Ecology
J. Z. Chen, D. M. Fowler, N. Tokuriki
Summary: Fitness landscapes are important concepts in evolutionary biochemistry, but measurements of phenotype-fitness landscapes in proteins are limited. In this study, we quantified the single mutational effects on fitness and phenotype of VIM-2 beta-lactamase across a range of ampicillin concentrations and constructed a phenotype-fitness landscape. Our findings suggest that the evolution of VIM-2 can be predicted based on the selection environment, providing new quantitative knowledge on the evolution of beta-lactamases and proteins in general.
NATURE ECOLOGY & EVOLUTION
(2022)
Article
Biochemistry & Molecular Biology
Charlotte M. Miton, Nobuhiko Tokuriki
Summary: Protein engineers have studied and borrowed from nature's tricks to accelerate protein evolution. However, our ability to generate new proteins in the laboratory seems limited. This Perspective explores the role of insertions and deletions (indels) in the functional diversification of proteins in nature and discusses their untapped potential for protein engineering.
Article
Infectious Diseases
Christopher Frohlich, Vidar Sorum, Nobuhiko Tokuriki, Pal Jarle Johnsen, Orjan Samuelsen
Summary: This study investigated the impact of cefiderocol on resistance development and the evolution of beta-lactamases from different Ambler classes. The expression of bla(KPC-2), bla(CMY-2), bla(CTX-M-15), and bla(NDM-1) significantly reduced cefiderocol susceptibility, while mutations in these enzymes further increased cefiderocol resistance. Resistance development also led to collateral changes in sensitivity to other beta-lactam drugs and functional trade-offs.
JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
(2022)
Article
Chemistry, Multidisciplinary
Morito Sakuma, Shingo Honda, Hiroshi Ueno, Kazuhito V. Tabata, Kentaro Miyazaki, Nobuhiko Tokuriki, Hiroyuki Noji
Summary: Enzymes display heterogeneity in their conformational and functional states, which is crucial for the evolution of new functions. A single-molecule enzyme assay was used to analyze functional substates in wild-type and mutant alkaline phosphatase. Mutant enzymes exhibited significantly heterogeneous functional substates, while the wild-type enzyme showed a highly homogeneous substate. The degree of functional substates correlated with the improvement in promiscuous activities. The findings highlight the importance of functional substates in enzyme evolution.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Biochemistry & Molecular Biology
Cindy T. T. Wei, Nicholas A. A. Popp, Omri Peleg, Rachel L. L. Powell, Elhanan Borenstein, Dustin J. J. Maly, Douglas M. M. Fowler
Summary: Researchers have developed a chemically activated DNA-binding Cas9 switch called ciCas9, which enables temporal control over seven Cas9 effectors including base editors and transcriptional activators. Using this switch, they analyzed the kinetics of base editing and found that editing occurs within hours and early rapid editing predicts the final editing magnitude. They also discovered that editing at preferred nucleotides increases bystander edits. The ciCas9 switch offers a versatile approach for generating chemically controlled Cas9 effectors and enables precise temporal effector control for kinetic studies.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Vanessa Nguyen, Ethan Ahler, Katherine A. Sitko, Jason J. Stephany, Dustin J. Maly, Douglas M. Fowler
Summary: Hsp90 is a molecular chaperone involved in the refolding and activation of protein substrates. By studying a large number of variants, we identified functionally dependent client variants of the Src kinase and identified the factors driving Hsp90 dependence.
Letter
Biotechnology & Applied Microbiology
Douglas M. Fowler, David J. Adams, Anna L. Gloyn, William C. Hahn, Debora S. Marks, Lara A. Muffley, James T. Neal, Frederick P. Roth, Alan F. Rubin, Lea M. Starita, Matthew E. Hurles, Nadav Ahituv, Orli G. Bahcal, Dustin Baldridge, Jonathan S. Berg, Alice H. Berger, Aisha Haley Bianchi, Benedetta Bolognesi, Michael Boutros, Steven Brenner, Matthew H. Brush, Vanessa Bryant, Carol J. Bult, Martha Bulyk, Melissa Call, Hannah Carter, Melina Claussnitzer, Feng Chen, Melissa S. Cline, Josh T. Cuperus, Moez Dawood, Hannah N. De Jong, Mafalda Dias, Michael Dunn, Jesse Engreitz, Kyle Farh, Phillip G. Febbo, Stanley Fields, Gregory M. Findlay, Helen Firth, James S. Fraser, Jonathan Frazer, Mattia Frontini, Irene Gallego Romero, Andrew M. Glazer, Murat Gueler, Rasmus Hartmann-Petersen, Richard Houlston, Kuan-Lin Huang, Carolyn M. Hutter, Sujatha Jagannathan, Richard G. James, Martin Kampmann, Rachel Karchin, Justin B. Kinney, Alexis C. Komor, Sriram Kosuri, Ben Lehner, Kresten Lindorff-Larsen, Zane Lombard, Daniel G. MacArthur, Maria Martin, Ultan McDermott, Shannon M. McNulty, Alex N. Nguyen Ba, Anne O'Donnell-Luria, Brian J. O'Roak, Victoria N. Parikh, Leopold Parts, Michael J. Pazin, Tina Pesaran, Slave Petrovski, Christine Queitsch, David E. Root, Jay Shendure, Amanda B. Spurdle, Kevin L. Taylor, Clare Turnbull, Judit Villen, L. E. L. M. Vissers, Alex H. Wagner, Matthew J. Wakefield, Jochen Weile, Jenny Xiao
Summary: Sequencing has identified numerous genetic variants in humans, but their functional effects remain largely unknown, hindering precision medicine. However, multiplexed variant effect assays can assess large numbers of variants simultaneously, generating variant effect maps that reveal the functional impact of every possible single nucleotide change. Creating an "Atlas" of variant effect maps for all protein encoding genes and regulatory elements in the human genome would revolutionize our understanding of genetics and enable advancements in therapeutics, human evolution, and disease diagnosis and treatment.
Article
Chemistry, Multidisciplinary
Morito Sakuma, Shingo Honda, Hiroshi Ueno, Kazuhito V. Tabata, Kentaro Miyazaki, Nobuhiko Tokuriki, Hiroyuki Noji
Summary: Enzymes have inherent heterogeneity in their conformational and functional states, which is key to the evolution of new functions. Single-molecule enzyme assays allow direct observation of these multiple functional substates. We analyzed functional substates in wild-type and mutant Escherichia coli alkaline phosphatase and found that mutant enzymes exhibited significantly heterogeneous functional substates, while the wild-type enzyme showed a highly homogeneous substate. Our study provides comprehensive evidence that functional substates can be easily altered by mutations and that the evolution towards new catalytic activities may involve modulation of these substates.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Michael Rappleye, Sarah J. Wait, Justin Daho Lee, Jamison C. Siebart, Lily Torp, Netta Smith, Jeanot Muster, Kenneth A. Matreyek, Douglas M. Fowler, Andre Berndt
Summary: Researchers have developed a high-throughput engineering platform called Opto-MASS that can test thousands of genetically encoded fluorescent indicators (GEFIs) variants in parallel in mammalian cells. They demonstrated the effectiveness of this system by rapidly engineering new sensors with distinct biophysical properties and significantly shortening the optimization time.
Review
Biochemistry & Molecular Biology
Christopher Frohlich, John Z. Chen, Sevan Gholipour, Ayse N. Erdogan, Nobuhiko Tokuriki
Summary: Beta-lactamases are a common resistance mechanism against beta-lactam antibiotics and have become important models in enzymology and evolutionary biochemistry. They have evolved multiple times from distinct evolutionary origins, exhibiting diverse structural features and enzymatic mechanisms. Understanding their evolution and diversity can aid various disciplines.
PROTEIN ENGINEERING DESIGN & SELECTION
(2021)