Review
Chemistry, Multidisciplinary
Cameron C. Hanna, Julia Kriegesmann, Luke J. Dowman, Christian F. W. Becker, Richard J. Payne
Summary: Lipidation is a common modification of peptides and proteins that can affect crucial biological activities. The use of synthetic techniques allows for the preparation of pure and homogeneously modified lipidated proteins, revealing the impact of these modifications on protein structure and function.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Multidisciplinary
Rebecca Notis Dardashti, Shay Laps, Jacob S. Gichtin, Norman Metanis
Summary: Human selenoprotein H, the only selenocysteine-containing protein located in the cell's nucleolus, is suggested to be involved in DNA binding, reactive oxygen species consumption, and cancer prevention. In this study, a semi-synthetic approach was used to obtain a mutated selenoprotein H and it was demonstrated to have sub-micromolar affinity for DNA binding using biolayer interferometry. The developed semi-synthetic approach can be applied for producing biologically and therapeutically relevant proteins.
Article
Chemistry, Organic
Yoshihiro Nishimoto, Masaki Fujie, Junki Hara, Makoto Yasuda
Summary: During the synthesis of novel hypervalent iodines, we observed a different regioselectivity in catalytic reactions compared to the common PhI(OAc)2, which was attributed to noncovalent interactions between sulfonyloxy groups and cationic heterocyclic moieties. This significant change in regioselectivity was revealed through observation of intermediates and density functional theory studies, including noncovalent interaction analysis.
ORGANIC CHEMISTRY FRONTIERS
(2021)
Article
Biochemical Research Methods
Jessica Sayers, Evans C. Wralstad, Ronald T. Raines
Summary: The ribonuclease S complex has led to historic discoveries in protein chemistry and enzymology, but its applications have been hindered by two main drawbacks: immune response in humans and susceptibility to dissociation. By semi-synthesizing an RNase S conjugate derived from human pancreatic ribonuclease and stabilized with a covalent interfragment cross-link, these limitations have been addressed, enabling unprecedented applications of the RNase-S system.
BIOCONJUGATE CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Lukas Kerul, Maximilian Schrems, Alanca Schmid, Rajeshwari Meli, Christian F. W. Becker, Claudia Bello
Summary: This study describes the establishment of a semi-synthesis strategy for the preparation of modified variants of G-CSF, addressing the issues of low solubility and aggregation. The successful preparation of G-CSF variants with biological activity in cell proliferation assays was achieved.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Biology
Hwan Bae, Thibault Viennet, Eunyoung Park, Nam Chu, Antonieta Salguero, Michael J. Eck, Haribabu Arthanari, Philip A. Cole
Summary: Akt is a protein kinase that plays a central role in metabolism and cancer. This study reveals the intensified autoinhibitory features of the R86A Akt mutant, which enhances the PH domain-kinase domain affinity. The key interaction network involving Arg86, Glu17, and Tyr18 is shown to control the conformation and activity of Akt, providing insights into the molecular basis of E17K Akt activation as an oncogenic driver.
Review
Chemistry, Multidisciplinary
Kohsuke Ohmatsu
Summary: This article summarizes the design and applications of ion-paired chiral ligands and chiral 1,2,3-triazolium salts, highlighting their use in controlling the selectivity in chemical transformations. Ion pairing strategies have proven to be versatile in constructing well-organized transition structures, making them valuable in catalyst design.
BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN
(2023)
Article
Multidisciplinary Sciences
Gerard Duart, Assaf Elazar, Jonathan Y. Weinstein, Laura Gadea-Salom, Juan Ortiz-Mateu, Sarel J. Fleishman, Ismael Mingarro, Luis Martinez-Gil
Summary: Several methods have been developed to explore protein-protein interactions, but there is a need for more research on targeting transmembrane domains (TMDs). This study developed a computational approach to design sequences that can modulate protein-protein interactions in the membrane, and successfully applied it to BclxL. The findings enhance our understanding of protein-protein interactions in membranes and may lead to the development of inhibitors targeting TMD interactions.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Review
Biology
Juan Ferrando, Lee A. Solomon
Summary: De novo protein design is a powerful methodology used to study natural functions in an artificial-protein context, reproducing reactions and uncovering biophysical principles difficult to extract from natural proteins. Natural proteins can bind ligands with high levels of specificity and affinity. Recent studies have focused on small molecules, nucleic acids, and protein-protein interactions, with advancements in structural design and computational modeling approaches.
Article
Biochemistry & Molecular Biology
Takatsugu Kosugi, Masahito Ohue
Summary: Over 930,000 protein-protein interactions (PPIs) have been identified, but targeting PPIs with conventional small molecules is challenging. A newly developed cyclic peptide complex offset, combined with AlphaFold2, can accurately predict the structure of target protein-cyclic peptide complexes and enable the design of putative cyclic peptide sequences targeting PPI.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Tao Wang, Sofia Sanz, Jesus Castro-Esteban, James Lawrence, Alejandro Berdonces-Layunta, Mohammed S. G. Mohammed, Manuel Vilas-Varela, Martina Corso, Diego Pena, Thomas Frederiksen, Dimas G. de Oteyza
Summary: This study characterized the magnetic states of chiral graphene nanoribbons by substitution of hydrogen atoms with ketones, leading to the generation of unpaired pi radicals that can interact via exchange coupling. The interactions between these radical states were found to depend significantly on factors such as chirality and the presence of ketone functionalization, and the parameters for accurately describing these systems within the mean-field Hubbard model were determined. Overall, this research provides insights for theoretically modeling and designing GNR-based nanostructures with tunable magnetic properties.
Review
Biochemistry & Molecular Biology
Christian Freund, Dirk Schwarzer
Summary: The transpeptidase sortase A of Staphylococcus aureus is utilized in protein chemistry for sortase-mediated ligation. The moderate catalytic efficiency and specificity of Sa-SrtA have led to the development of new biocatalysts through screening of variants and directed protein evolution. This has resulted in sortases with enhanced catalytic activity and recognition of new sorting motifs.
Review
Chemistry, Multidisciplinary
Xuefei Wang, Duan Ni, Yaqin Liu, Shaoyong Lu
Summary: This review summarizes drug design strategies for protein-protein interactions (PPIs) targeting, specifically focusing on the development of peptide-based PPI inhibitors. Examples targeting well-known PPI targets such as Bcl-2 family members, p53-MDM2, and APC-Asef are presented to illustrate detailed schemes for peptide-based PPI inhibitor development and optimization. The review provides an overview of recent advances in drug discovery targeting PPIs through peptides or peptidomimetics, offering insights into future therapeutic agent development for historically challenging PPI systems.
FRONTIERS IN CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Serena Fiorito, Francesco Epifano, Lorenzo Marchetti, Salvatore Genovese
Summary: Selenium-containing compounds are gaining interest for their potential pharmacological properties, particularly as anticancer and antioxidant agents. This study reports the synthesis of the first Se-phenylpropanoids, which showed greater antioxidant and radical scavenging activity compared to the parent compound auraptene. The described procedure offers an easy-to-handle method for synthesizing selenium analogues of naturally occurring biologically active compounds.
Editorial Material
Biochemistry & Molecular Biology
Scott N. Lyons, Xiaolu A. Cambronne
Summary: The ChemoX platform has revolutionized biosensor development by eliminating the need for optimization with each new iteration and enabling versatile applications and optimized readouts through unique Forster resonance energy transfer pairings.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Aiwei Wu, Junhong Zhi, Tian Tian, Ali Cihan, Murat A. Cevher, Ziling Liu, Yael David, Tom W. Muir, Robert G. Roeder, Ming Yu
Summary: The study showed that DOT1L depletion in erythroleukemic cells does not affect the elongation rate of RNA polymerase II, but plays a significant role in transcription initiation by regulating the recruitment of transcription factor IID along with ENL. This is achieved by enhancing H2Bub1 levels and limiting the recruitment of the SAGA complex. These findings provide new insights into the role of the DOT1L complex in transcriptional regulation and its implications for MLLr leukemias.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Nazar Mashtalir, Hai T. Dao, Akshay Sankar, Hengyuan Liu, Aaron J. Corin, John D. Bagert, Eva J. Ge, Andrew R. D'Avino, Martin Filipovski, Brittany C. Michel, Geoffrey P. Dann, Tom W. Muir, Cigall Kadoch
Summary: This study identified the effects of chromatin features on mSWI/SNF activities and interactions, as well as the combinatorial contributions of complex module components, reader domains, and nucleosome engagement properties to the localization of complexes.
Article
Chemistry, Multidisciplinary
Hai T. Dao, Hengyuan Liu, Nazar Mashtalir, Cigall Kadoch, Tom W. Muir
Summary: This study reports a strategy for controlling the orientation of asymmetric nucleosomes and hexasomes, providing an efficient method for studying gene regulation. By using truncated DNA templates and DNA ligation, the researchers successfully prepared desymmetrized mononucleosomes and oligonucleosomes with varied DNA sequences and histone compositions. Using this technology, they investigated the impact of asymmetry on chromatin remodeling and found that cancer-associated histone mutations can cause aberrant chromatin structure.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Multidisciplinary
Bradley J. Lukasak, Robert E. Thompson, Michelle M. Mitchener, Vanessa J. Feng, John D. Bagert, Tom W. Muir
Summary: In this study, the SpyCatcher/SpyTag system was used to assemble desymmetrized nucleoprotein complexes. This method allows for the generation of nucleosomes with asymmetric modifications and facilitates the investigation of the effects of nucleosome asymmetry on chromatin remodeling processes and histone enzyme activity.
ACS CENTRAL SCIENCE
(2022)
Article
Biotechnology & Applied Microbiology
H. Tomas Rube, Chaitanya Rastogi, Siqian Feng, Judith F. Kribelbauer, Allyson Li, Basheer Becerra, Lucas A. N. Melo, Bach Viet Do, Xiaoting Li, Hammaad H. Adam, Neel H. Shah, Richard S. Mann, Harmen J. Bussemaker
Summary: This study presents a flexible machine learning method called ProBound, which accurately predicts the binding affinity or kinetic rates of protein-ligand interactions based on sequencing data. ProBound quantifies the behavior of transcription factors, captures the impact of DNA modifications and conformational flexibility, and infers specificity directly from in vivo data. It opens new avenues for decoding biological networks and rationally engineering protein-ligand interactions.
NATURE BIOTECHNOLOGY
(2022)
Article
Biology
Frank Hidalgo, Laura M. Nocka, Neel H. Shah, Kent Gorday, Naomi R. Latorraca, Pradeep Bandaru, Sage Templeton, David Lee, Deepti Karandur, Jeffrey G. Pelton, Susan Marqusee, David Wemmer, John Kuriyan, Amy Andreotti
Summary: Cancer mutations in Ras occur predominantly at three hotspots: Gly 12, Gly 13, and Gln 61. This study reveals the importance of GAP surveillance and protein stability in determining the sensitivity of Ras to mutational activation, as well as distinguishing the cancer hotspots from other activating mutations.
Article
Multidisciplinary Sciences
Aishan Zhao, Steven P. Bodine, Qian Xie, Boyuan Wang, Geeta Ram, Richard P. Novick, Tom W. Muir
Summary: This study reveals the involvement of membrane protease regulator of agr QS (MroQ) in the production of autoinducing peptide (AIP) in Staphylococcus aureus. It also uncovers the different roles of MroQ in different agr specificity groups, enhancing our understanding of the agr response and Staphylococcus aureus virulence.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Chemistry, Multidisciplinary
Giridhar Sekar, Adam J. Stevens, Anahita Z. Mostafavi, Pulikallu Sashi, Tom W. Muir, David Cowburn
Summary: Split intein-mediated protein trans-splicing (PTS) is a widely used method in chemical biology and biotechnology for traceless and specific protein ligation. The efficiency of PTS can be limited by external residues flanking the intein. In this study, a recently developed atypically split intein (Cat) was further modified to enhance its PTS activity in the presence of unfavorable N-extein residues. The mechanism behind the enhanced activity was explored using nuclear magnetic resonance spectroscopy and molecular dynamics simulations, highlighting the contribution of a conserved histidine residue. This enhanced extein tolerance of Cat* expands the applicability of atypically split inteins and reveals common principles of extein dependence.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Review
Biochemistry & Molecular Biology
Michelle M. Mitchener, Tom W. Muir
Summary: Research over the past decade has revealed a new layer of epigenetic dysregulation, uncovering the association between somatic missense mutations in histones and human pathologies, especially cancer. While some of these mutations are believed to be key drivers of cancer, the effects of the majority of them on disease onset and progression are still unclear. Studies have shown that even at low dosage, histone mutants can corrupt chromatin states, providing insights into the intricate mechanisms of epigenetic control.
Article
Biochemistry & Molecular Biology
Helen T. Hobbs, Neel H. Shah, Sophie R. Shoemaker, Jeanine F. Amacher, Susan Marqusee, John Kuriyan
Summary: Using ancestral sequence reconstruction and deep mutational scanning, we have generated high-yield Syk-family kinase variants that can be expressed in bacteria. We have also developed a novel two-hybrid assay for screening and studying the function of this kinase.
Article
Chemistry, Multidisciplinary
Christopher W. Lamartina, Cassandra A. Chartier, Sumin Lee, Neel H. Shah, Tomislav Rovis
Summary: Here, a modular peptide ligation methodology is reported, which uses Rh(III) catalysis to couple dioxazolones, arylboronic acids, and acrylamides to construct amide bonds in a diastereoselective manner under mild conditions. The method shows excellent functional group tolerance and a large substrate scope, allowing for the construction of unnatural amino acid residues. This methodology is demonstrated in the synthesis of diastereomeric proteasome inhibitor analogs and the ligation of oligopeptides to construct a polypeptide with an unnatural residue.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Biochemistry & Molecular Biology
Suk ho Hong, Sarah Y. Xi, Andrew C. Johns, Lauren C. Tang, Allyson Li, Madeleine N. Hum, Cassandra A. Chartier, Marko Jovanovic, Neel H. Shah
Summary: Protein tyrosine phosphatases (PTPs) are essential enzymes that regulate cellular processes and are dysregulated in disease states. This study explores various chemical compounds for covalent inhibition of tyrosine phosphatases, providing insights into their potency and specificity. The findings can inspire the development of new probes and inhibitors for tyrosine phosphatases.
Article
Biology
Allyson Li, Rashmi Voleti, Minhee Lee, Dejan Gagoski, Neel H. Shah
Summary: Tyrosine kinases and SH2 domains have specific binding preferences based on the surrounding amino acid sequence of the target tyrosine residue. A platform combining genetic peptide libraries and deep sequencing was developed to study sequence recognition by these domains. The method accurately predicted phosphorylation rates and identified mutations that affect tyrosine kinase recognition. It also assessed the impact of non-canonical and post-translationally modified amino acids on sequence recognition.
Meeting Abstract
Immunology
Yuan-Li Tsai, Marcel Arias Badia, Theresa A. Kadlecek, Neel H. Shah, Lawrence Fong, Arthur Weiss
JOURNAL OF IMMUNOLOGY
(2022)
Review
Chemistry, Multidisciplinary
Ciaran P. Seath, Aaron D. Trowbridge, Tom W. Muir, David W. C. MacMillan
Summary: Biomolecular interactions are crucial for cellular processes, with a focus on protein-protein interactions playing a key role in cellular signaling pathways. Recent advancements in creating reactive intermediates that cross-link neighboring proteins have provided insights into the biomolecular makeup of cellular environments, accelerating the understanding of PPIs and their impact on cellular physiology.
CHEMICAL SOCIETY REVIEWS
(2021)
