Article
Chemistry, Medicinal
Juan Xie, Shiwei Wang, Youjun Xu, Minghua Deng, Luhua Lai
Summary: This study analyzed dominant motion modes to determine motion correlations between allosteric and orthosteric sites, finding that such correlations are dominated by either fast or slow vibrational modes. The developed prediction tool CorrSite2.0 outperformed other methods in predicting allosteric sites, providing a powerful tool for allosteric drug and protein design.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Biochemistry & Molecular Biology
Shanker S. S. Panchapakesan, Ronald R. Breaker
Summary: The RNA World theory suggests that sophisticated ribozymes and riboswitches played a key role in metabolic processes in ancient organisms, and various types of catalytic RNAs and ligand-sensing RNA switches still exist in modern cells. However, the fusion of RNA enzyme and RNA switch components to form allosteric ribozymes is rare in today's biological systems, despite the abundance of self-cleaving ribozymes and riboswitch aptamers.
NATURE CHEMICAL BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Dongxue Yang, Eric Gouaux
Summary: This study used cryo-electron microscopy structures to elucidate the structural states of SERT in different conditions, revealing all fundamental steps of the transport cycle. The research identified the substrate-bound allosteric site and provided new structural insights into how SERT controls the binding and unbinding of serotonin.
Article
Multidisciplinary Sciences
Gemma Fisher, Marina Corbella, Magnus S. Alphey, John Nicholson, Benjamin J. Read, Shina C. L. Kamerlin, Rafael G. da Silva
Summary: ATP phosphoribosyltransferase, the first step of histidine biosynthesis, is regulated by a complex allosteric mechanism. The regulatory protein HisZ enhances catalysis by the catalytic protein HisG(S) and mediates allosteric inhibition by histidine. This study demonstrates that HisZ can restore the impaired catalytic activity of HisG(S) mutants through allosteric interactions, even though the HisZ:HisG(S) interaction site is located far from the active site.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Medicinal
Ying Yang, Lei Zhang, Jinying Tian, Fei Ye, Zhiyan Xiao
Summary: A hierarchical virtual screening identified four potential PTP1B inhibitors with distinct structures, among which H3 and H9 showed selectivity to PTP1B. Key residues responsible for potent allosteric inhibition and excellent PTP selectivity were identified through molecular dynamics simulations and MM-GBSA calculations, aiding future molecular design of PTP1B allosteric inhibitors.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Chemistry, Physical
Mauro L. Mugnai, D. Thirumalai
Summary: The SARS-CoV-2 virus recognizes the ACE2 enzyme by binding with its receptor binding domain (RBD), and the dissociation of the ACE2-RBD complex triggers an allosteric signal. Through the use of an Elastic Network Model (ENM) and Structural Perturbation Method (SPM), it has been found that the dissociation of the complex opens the ACE2 substrate-binding cleft and that RBD binding facilitates fluctuations in the ACE2 binding cleft. These findings provide a structural and dynamical understanding of how SARS-CoV-2 affects ACE2 enzymatic activity, and a conserved glycine (G502 in SARS-CoV-2) has been identified as a key participant in complex disassembly.
JOURNAL OF CHEMICAL PHYSICS
(2023)
Article
Biochemistry & Molecular Biology
Daniel L. De la Cruz, Laszlo Prokai, Katalin Prokai-Tatrai
Summary: Through the use of a homology model and optimization of binding sites, this study revealed an allosteric binding site for a TRH antagonist on the TRH receptor, rather than the active site. This allosteric site exhibited stronger binding affinity and has the potential to play a significant role in agonist and antagonist actions.
Article
Biochemistry & Molecular Biology
Hengxi Zhang, Carlos Modenutti, Yelha Phani Kumar Nekkanti, Maxime Denis, Iris A. Bermejo, Jonathan Lefebre, Kateryna Che, Dongyoon Kim, Marten Kagelmacher, Dennis Kurzbach, Marc Nazare, Christoph Rademacher
Summary: This study investigated the exact binding site of human and murine homologues of Langerin using structural comparison and molecular dynamics simulations. It was found that the nonconserved short loops exhibited a high degree of conformational flexibility between the two homologues. Sequence analysis and mutational studies identified a pair of residues essential for recognizing thiazolopyrimidines. By utilizing solvent paramagnetic relaxation enhancement NMR studies and a series of peptides, the allosteric binding site for these aromatic heterocycles was determined to be the cleft between the short and long loops.
ACS CHEMICAL BIOLOGY
(2022)
Article
Pharmacology & Pharmacy
Risa Okimoto, Katsutoshi Ino, Kenichiro Ishizu, Hajime Takamatsu, Kazuyuki Sakamoto, Hironori Yuyama, Hideyoshi Fuji, Akiyoshi Someya, Akiyoshi Ohtake, Takao Ishigami, Noriyuki Masuda, Masahiro Takeda, Shunichi Kajioka, Naoki Yoshimura
Summary: The novel M-3 receptor positive allosteric modulator ASP8302 enhances human M-3 receptor activation by interacting with a residue distinct from reported allosteric sites, suggesting not only a novel allosteric site of M-3 receptors but also potential application in diseases caused by insufficient M-3 receptor activation. This finding provides significant insight into further research on the allosteric modulation mechanism of M-3 and other muscarinic receptors.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2021)
Article
Engineering, Geological
Richard J. Bathurst, Fahimeh M. Naftchali
Summary: This study quantitatively examines the influence of uncertainty in the estimation of geosynthetic reinforcement stiffness on numerical outcomes. Analytical solutions are used to determine the maximum deformation, reinforcement loads and strain, and mobilized reinforcement stiffness under different conditions. The paper also explores the relationship between deterministic design practices and probabilistic frameworks in terms of safety margins. Additionally, the practical benefits of using product-specific isochronous secant stiffness data are highlighted.
GEOTEXTILES AND GEOMEMBRANES
(2023)
Article
Biochemistry & Molecular Biology
Emily Chen, Krystle Reiss, Dilip Shah, Ramu Manjula, Brandon Allen, Eva L. Murphy, James W. Murphy, Victor S. Batista, Vineet Bhandari, Elias J. Lolis, George P. Lisi
Summary: Despite the low sequence identity, the study revealed a conserved dynamic regulatory network between MIF and MIF-2, with the structural basis of an allosteric site in MIF-2 being established. Molecular simulations showed a comparable hydrogen bond network in MIF-2, suggesting its influence on catalytic activity through modulating allosteric coupling. Disruption of the allosteric relay in MIF-2 attenuated enzymatic activity in vitro and receptor activation in vivo, indicating a conserved point of control for nonoverlapping functions in the MIF superfamily.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Lara Toy, Max E. Huber, Maximilian F. Schmidt, Dorothee Weikert, Matthias Schiedel
Summary: Fluorescently labeled ligands are versatile tools for studying GPCRs. In this study, TAMRA-labeled CCR2 ligands were designed and a fluorescent CCR2 ligand was developed for binding studies and fragment-based screening approaches.
ACS CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Lara Toy, Max E. Huber, Maximilian F. Schmidt, Dorothee Weikert, Matthias Schiedel
Summary: This article reports the structure-based development of fluorescent ligands targeting the intracellular allosteric binding site of CCR2, a class A GPCR that has been pursued as a drug target. By designing and synthesizing several TAMRA-labeled CCR2 ligands and testing their suitability as fluorescent reporters, the authors developed a promising tool, ligand 14, for future studies of CCR2 pharmacology, as well as for fragment-based screening approaches.
ACS CHEMICAL BIOLOGY
(2022)
Article
Pharmacology & Pharmacy
Qiufen Zhang, Yingyi Chen, Duan Ni, Zhimin Huang, Jiacheng Wei, Li Feng, Jun-Cheng Su, Yingqing Wei, Shaobo Ning, Xiuyan Yang, Mingzhu Zhao, Yuran Qiu, Kun Song, Zhengtian Yu, Jianrong Xu, Xinyi Li, Houwen Lin, Shaoyong Lu, Jian Zhang
Summary: This study identified a cryptic allosteric site, named Pocket Z, that is induced by the bi-directional allosteric signal triggered by NAD+ binding. Based on Pocket Z, researchers discovered a potent and selective allosteric inhibitor of SIRT6 called JYQ-42. JYQ-42 effectively inhibits SIRT6 deacetylation and demonstrates potential in suppressing cancer cell migration and pro-inflammatory cytokine production.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Energy & Fuels
Theophile Vitoussia, Alain Brillard, Damaris Kehrli, Alexis Kemajou, Ebenezer Njeugna, Jean-Francois Brilhac
Summary: The thermal degradation profiles and kinetic parameters of pellets made from three Cameroonian biomass were studied through pyrolysis and combustion processes. The results were compared to the base materials to assess the thermal behavior of the pellets.
BIOMASS CONVERSION AND BIOREFINERY
(2021)
