Article
Biochemistry & Molecular Biology
Leonore Novak, Maria Petrosino, Daniele Santorelli, Roberta Chiaraluce, Valerio Consalvi, Alessandra Pasquo, Carlo Travaglini-Allocatelli
Summary: A Phi value analysis was conducted on BRD2(2) to investigate its folding pathway, revealing that the C-terminal region serves as the initial folding nucleus, with the N-terminal region consolidating its structure later in the process. This indicates a hierarchical mechanism of protein folding with non-native interactions playing a significant role.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Wanyue Xu, Jingjie Xu, Caiping Shi, Jing Wu, Huaxia Wang, Wei Wu, Xiangjun Chen, Lidan Hu
Summary: This study identified a novel mutation (Ile82Met) in gamma A-crystallin and investigated its potential molecular mechanism in cataract. The mutation was found to decrease protein stability and increase aggregatory potency under stressful conditions. Furthermore, chemical denaturation affected the unfolding process of gamma A-crystallin.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2022)
Article
Multidisciplinary Sciences
Il-Soo Park, Seongchan Kim, Yeajee Yim, Ginam Park, Jinahn Choi, Cheolhee Won, Dal-Hee Min
Summary: This study reports the creation of a synthetic chaperone to control the folding of therapeutic peptides and demonstrates its enhanced therapeutic potential in a tumor model. The synthetic chaperone, based on porous nanoparticles, provides an internal hydrophobic environment which stabilizes the secondary structure of the encapsulated peptides. Additionally, the modified nanoparticles serve as a nanoreactor and effectively deliver the stabilized peptides into cancer cells, resulting in inhibition of cancer growth.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
R. Charlotte Eccleston, David D. Pollock, Richard A. Goldstein
Summary: Epistasis and cooperativity in protein folding are both influenced by networks of energetic interactions within proteins, and their selection can affect each other. Selection for cooperativity may be crucial for predicting protein structure using epistasis measurements.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Endocrinology & Metabolism
Balamurugan Dhayalan, Deepak Chatterjee, Yen-Shan Chen, Michael A. Weiss
Summary: Analysis of diabetes-associated mutations in the human insulin gene has provided insights into the folding mechanisms of proinsulin, revealing the impact of mutations on pancreatic beta-cell dysfunction and insulin secretion. Studies suggest that conserved residues play a crucial role in folding efficiency and the susceptibility of proinsulin to impaired foldability can contribute to the development of diseases. This highlights the molecular links between biophysical principles and the impact on diseases such as diabetes and obesity.
FRONTIERS IN ENDOCRINOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Patrick Bryant, Arne Elofsson
Summary: This article describes a computational method for designing peptide binders towards specific protein interfaces. By combining multiple methods, including Foldseek, ESM-IF1, and AlphaFold2, the researchers developed a peptide binder design tool and demonstrated its ability to improve the success rate.
COMMUNICATIONS CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Anastassia Andreevna Vorobieva
Summary: After decades of progress in computational protein design, the focus has now shifted towards designing proteins that fold and function in lipid membranes. Successful de novo designs of simplified model membrane protein systems have helped elucidate fundamental principles of protein folding and interaction in the hydrophobic lipid environment. New methodological innovations, including machine learning approaches and experimental techniques, offer opportunities for advancing membrane protein design.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Tae-Eun Kim, Kotaro Tsuboyama, Scott Houliston, Cydney M. Martell, Claire M. Phoumyvong, Alexander Lemak, Hugh K. Haddox, Cheryl H. Arrowsmith, Gabriel J. Rocklin
Summary: Designing new protein structures remains challenging, and our study successfully designed stable aPPa proteins through large-scale design and test cycles, shedding light on the biophysical determinants of folding.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Chemistry, Medicinal
Gianni Chessari, Ian R. Hardcastle, Jong Sook Ahn, Burcu Anil, Elizabeth Anscombe, Ruth H. Bawn, Luke D. Bevan, Timothy J. Blackburn, Ildiko Buck, Celine Cano, Benoit Carbain, Juan Castro, Ben Cons, Sarah J. Cully, Jane A. Endicott, Lynsey Fazal, Bernard T. Golding, Roger J. Griffin, Karen Haggerty, Suzannah J. Harnor, Keisha Hearn, Stephen Hobson, Rhian S. Holvey, Steven Howard, Claire E. Jennings, Christopher N. Johnson, John Lunec, Duncan C. Miller, David R. Newell, Martin E. M. Noble, Judith Reeks, Charlotte H. Revill, Christiane Riedinger, Jeffrey D. St Denis, Emiliano Tamanini, Huw Thomas, Neil T. Thompson, Mladen Vinkovic, Stephen R. Wedge, Pamela A. Williams, Nicola E. Wilsher, Bian Zhang, Yan Zhao
Summary: In this study, novel isoindolinone-based MDM2 inhibitors were designed with rational structure guidance and showed potent inhibition of MDM2-p53 interaction, leading to cytostasis in an osteosarcoma xenograft model. These findings highlight the potential of targeting MDM2 in cancer therapy.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Irena Roterman, Katarzyna Stapor, Dawid Dulak, Leszek Konieczny
Summary: The experimentally determined structures of amyloid forms are primarily characterized by the two-dimensional forms of a single polypeptide chain, which is made possible by the beta structure and the numerous hydrogen bonds. This study proposes a possible mechanism for obtaining such a structure based on the geometric characterization of the polypeptide chain and molecular dynamics results. The potential mechanism of amyloid transformation is presented using transthyretin and amyloid A beta as examples.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Analytical
Dong-Hwa Lee, Sohee Oh, Kyungeun Lim, Boah Lee, Gwan-Su Yi, Young-Rok Kim, Ki-Bum Kim, Chong-Kil Lee, Seung-Wook Chi, Mi-Kyung Lee
Summary: Bacterial riboswitch RNAs are potential targets for novel antibiotics against antibiotic-resistant superbacteria. This study demonstrated the specific interaction between the adenine-sensing riboswitch aptamer domain and adenine at the single-molecule level using alpha-hemolysin nanopores, which could be a valuable platform for ultrasensitive drug screening against therapeutic RNA targets.
ANALYTICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Alessia Ruggiero, Han-Gyu Choi, Giovanni Barra, Flavia Squeglia, Young Woo Back, Hwa-Jung Kim, Rita Berisio
Summary: The HtpG(Mtb) protein in tuberculosis vaccines is a dimeric nucleotide-binding protein with antigenic properties. The immune response is mainly elicited by the C-terminal and middle domains of the protein. This information can be used to design more stable, easily produced, and effective vaccine antigens.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Marianne Defresne, Sophie Barbe, Thomas Schiex
Summary: Computational Protein Design has achieved impressive results by using Deep Learning technology, but there is still no consensus on the most suitable representations of protein data, requiring further research and discussion.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemical Research Methods
Chad D. Hyer, Hsien-Jung L. Lin, Connor T. Haderlie, Monica Berg, John C. Price
Summary: The structure of a protein defines its function and integrity, and quantifying protein folding stability (PFS) is crucial for understanding disease mechanisms. However, the lack of a user-friendly data processing tool has hindered PFS studies. We present C-Half, a user-friendly software with a graphical interface for calculating PFS, and expect its introduction to promote the usage of PFS in research.
JOURNAL OF PROTEOME RESEARCH
(2023)
Article
Multidisciplinary Sciences
Joseph L. Harman, Patrick N. Reardon, Shawn M. Costello, Gus D. Warren, Sophia R. Phillips, Patrick J. Connor, Susan Marqusee, Michael J. Harms
Summary: This study identified a mutation in S100A9 protein that simultaneously increased its stability and disrupted its natural ability to regulate Toll-like receptor 4. Structural analysis revealed that the mutation distorted the hydrophobic binding surface of the protein, leading to its functional impairment. Bioinformatic analysis further showed that Phe residues at both positions 37 and 63 are rarely found in S100A9 proteins from different organisms, suggesting that avoiding pathological stabilizing interactions constrains the evolution of S100A9.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Matthias R. Bauer, Andreas Kraemer, Giovanni Settanni, Rhiannon N. Jones, Xiaomin Ni, Raysa Khan Tareque, Alan R. Fersht, John Spencer, Andreas C. Joerger
ACS CHEMICAL BIOLOGY
(2020)
Article
Oncology
Xin Zhang, Tim Zegar, Tim Weiser, Feda H. Hamdan, Benedict-Tilman Berger, Romain Lucas, Dimitrios-IIias Balourdas, Swetlana Ladigan, Phyllis F. Cheung, Sven-Thorsten Liffers, Marija Trajkovic-Arsic, Bjoern Scheffler, Andreas C. Joerger, Stephan A. Hahn, Steven A. Johnsen, Stefan Knapp, Jens T. Siveke
INTERNATIONAL JOURNAL OF CANCER
(2020)
Article
Biochemistry & Molecular Biology
Flora Doffe, Vincent Carbonnier, Manon Tissier, Bernard Leroy, Isabelle Martins, Johanna S. M. Mattsson, Patrick Micke, Sarka Pavlova, Sarka Pospisilova, Jana Smardova, Andreas C. Joerger, Klas G. Wiman, Guido Kroemer, Thierry Soussi
Summary: Infrequent and rare genetic variants in the human population outnumber common ones significantly. The TP53 coding region shows far more polymorphism than previously thought and presents high ethnic diversity. Analyses of new missense TP53 variants revealed they are benign and do not display loss of function compared to the normal TP53 gene.
CELL DEATH AND DIFFERENTIATION
(2021)
Article
Chemistry, Medicinal
Sandra Roehm, Martin Schroeder, Jessica E. Dwyer, Caroline S. Widdowson, Apirat Chaikuad, Benedict-Tilman Berger, Andreas C. Joerger, Andreas Kraemer, Jule Harbig, Daniel Dauch, Mark Kudolo, Stefan Laufer, Mark C. Bagley, Stefan Knapp
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Chemistry, Medicinal
Marek Wanior, Franziska Preuss, Xiaomin Ni, Andreas Kraemer, Sebastian Mathea, Tamara Goebel, David Heidenreich, Svenja Simonyi, Astrid S. Kahnt, Andreas C. Joerger, Stefan Knapp
JOURNAL OF MEDICINAL CHEMISTRY
(2020)
Article
Biochemistry & Molecular Biology
Claudio Luparello, Ilenia Cruciata, Andreas C. Joerger, Cory A. Ocasio, Rhiannon Jones, Raysa Khan Tareque, Mark C. Bagley, John Spencer, Martin Walker, Carol Austin, Tiziana Ferrara, Pietro D' Oca, Rossella Bellina, Rossella Branni, Fabio Caradonna
Summary: Carbazole compounds PK9320 and PK9323, as second-generation analogues of PK083, have been shown to restore p53 signaling in cancer cells by binding to mutation-induced surface crevices. The study demonstrates that small modifications in carbazole substitution patterns can significantly impact their genotoxic and epigenetic properties, with PK9320 and PK9323 being potential candidates for anticancer and epi-compounds.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Marek Wanior, Andreas Kraemer, Stefan Knapp, Andreas C. Joerger
Summary: SWI/SNF complexes are crucial epigenetic regulators of gene transcription, with a high mutation prevalence in human cancers driving oncogenic programs. SWI/SNF-mutant cancers are hypersensitive to perturbations in other subunits and biological pathways, offering potential for sustained anticancer effects. Exploiting these vulnerabilities through targeted therapy strategies, such as proteolysis targeting chimeras, can induce synthetic lethality in SWI/SNF-deficient cancers.
Article
Chemistry, Medicinal
Sandra Roehm, Benedict-Tilman Berger, Martin Schroeder, Deep Chatterjee, Sebastian Mathea, Andreas C. Joerger, Daniel M. Pinkas, Joshua C. Bufton, Amelie Tjaden, Lohitesh Kovooru, Mark Kudolo, Christian Pohl, Alex N. Bullock, Susanne Mueller, Stefan Laufer, Stefan Knapp
Summary: In this study, a potent and cell-active dual DDR/p38 chemical probe was developed, along with a structurally related negative control, for studying DDR kinase signaling. The structure-guided design approach provided insights into the folding process of p38 and how non-conserved amino acids modulate inhibitor selectivity. The developed DDR/p38 probe is a valuable tool for investigating the role of DDR kinase in normal physiology and disease development.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Roberta Tesch, Marcel Rak, Monika Raab, Lena M. Berger, Thales Kronenberger, Andreas C. Joerger, Benedict-Tilman Berger, Ismahan Abdi, Thomas Hanke, Antti Poso, Klaus Strebhardt, Mourad Sanhaji, Stefan Knapp
Summary: Salt-inducible kinases (SIKs) are crucial metabolic regulators, with their imbalance linked to various cancers. Researchers have optimized a kinase inhibitor to target SIK specifically, providing a potential new approach for cancer therapy by combining SIK inhibitors with traditional chemotherapeutic agents like paclitaxel.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Cell Biology
Qiang Zhang, Dimitrios-Ilias Balourdas, Bruno Baron, Alon Senitzki, Tali E. Haran, Klas G. Wiman, Thierry Soussi, Andreas C. Joerger
Summary: The extremophile Alvinella pompejana, an annelid worm living near hydrothermal vents in the Pacific Ocean, has a p53 family gene with a highly thermostable DNA-binding domain, which may play a crucial role in maintaining genome integrity.
CELL DEATH & DISEASE
(2022)
Article
Chemistry, Medicinal
Javier R. Balboa, Dominik J. Essig, Sana Ma, Nichlas Karer, Louise S. Clemmensen, Soren W. Pedersen, Andreas C. Joerger, Stefan Knapp, Soren Ostergaard, Kristian Stromgaard
Summary: The complex of NMDAR, nNOS, and PSD-95 is an important therapeutic target for acute ischemic stroke. By designing a cyclic nNOS β-hairpin mimetic peptide and generating peptide arrays, a potent inhibitor of the nNOS/PSD-95 interaction was identified.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Xiaomin Ni, Andreas C. Joerger, Apirat Chaikuad, Stefan Knapp
Summary: FUBP-interacting repressor (FIR) is a suppressor of the proto-oncogene MYC's transcription, by binding to the far upstream element (FUSE) of the MYC promoter. Competition with FUSE-binding protein 1 (FUBP1) is a crucial mechanism for MYC transcriptional regulation.
Article
Biochemical Research Methods
Maeva M. Pichon, Dawid Drelinkiewicz, David Lozano, Ruxandra Moraru, Laura J. Hayward, Megan Jones, Michael A. Mccoy, Samuel Allstrum-Graves, Dimitrios-Ilias Balourdas, Andreas C. Joerger, Richard J. Whitby, Stephen M. Goldup, Neil Wells, Graham J. Langley, Julie M. Herniman, Matthias G. J. Baud
Summary: Protein arylation using 2-sulfonylpyrimidines as covalent warheads for selective and metal-free cysteine S-arylation was evaluated. The reaction resulted in stable S-heteroarylated adducts at neutral pH. Fine-tuning of the heterocyclic core and exocyclic leaving group allowed predictable reactivity, covering >9 orders of magnitude. This study provides a comprehensive structure-reactivity relationship on heteroaryl sulfones and highlights 2-sulfonylpyrimidine as a synthetically tractable and protein compatible covalent motif for targeting reactive cysteines.
BIOCONJUGATE CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Joseph R. Stephenson Clarke, Leon R. Douglas, Patrick J. Duriez, Dimitrios-Ilias Balourdas, Andreas C. Joerger, Raniya Khadiullina, Emil Bulatov, Matthias G. J. Baud
Summary: The tumor suppressor protein p53 is inactivated in the majority of human cancers, and the Y220C mutant is one of the most prevalent p53 mutants. This study presents the development of high-affinity small molecules to stabilize p53-Y220C, marking an important milestone in the search for effective anticancer therapies.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Muhammad Ali, Mishal Mariam McAuley, Susanne Luechow, Stefan Knapp, Andreas C. Joerger, Ylva Ivarsson
Summary: PDZ domains are a large family of modular domains known for binding C-terminal motifs of target proteins, but the interaction involving internal PDZ binding motifs (PDZbms) remains poorly studied. Using the PDZ domain of Shank1 as a model, this study explored internal PDZbm-mediated interactions, expanding the interactome of Shank1 and indicating a largely unexplored interaction space of PDZ domains. The findings revealed that both C-terminal and internal PDZbm interactions can occur in the context of full-length proteins, and the affinities of PDZbm interactions are in the low micromolar range.
CURRENT RESEARCH IN STRUCTURAL BIOLOGY
(2021)