Article
Biochemistry & Molecular Biology
Huixia Wang, Wanhui Hu, Dongsheng Liu, Kurt Wuthrich
Summary: GLP-1R and GCGR are human receptors activated by GLP-1 and GCG, involved in metabolism regulation. NMR studies provide insights into their molecular structures and interactions with ligands.
Review
Endocrinology & Metabolism
Ellen Conceicao-Furber, Tamer Coskun, Kyle W. Sloop, Ricardo J. Samms
Summary: A major challenge of obesity therapy is to sustain clinically relevant weight loss over time. While effective anorectic agents have been developed, there is currently a lack of medications that effectively increase metabolic rate for weight loss. Activation of the GCGR has shown potential in increasing energy expenditure and augmenting the effects of other anti-obesity agents.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Biochemical Research Methods
Brittany N. Thomas, Abby L. Parrill, Daniel L. Baker
Summary: G protein-coupled receptors (GPCR) are the largest family of cell surface receptors in vertebrates and play a crucial role in pharmaceutical development. This study compares the docking performance of ligands with different functions into different GPCR activation states. The results show that the docking performance can be estimated in advance based on the docking target structure activation states, with potential improvements through receptor conformational adjustments.
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
(2022)
Article
Cell Biology
Xuanxuan Bai, Jianxin Jia, Qi Kang, Yadong Fu, You Zhou, Yingbin Zhong, Chao Zhang, Mingyu Li
Summary: The study demonstrates that GCGR plays an essential role in regulating glucose, amino acid, and lipid metabolism, with GCGR deficiency leading to alterations in amino acid and lipid metabolism in zebrafish. The findings suggest that GCGR is involved in modulating metabolic pathways and physiological processes in organisms.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Pharmacology & Pharmacy
Lijun Shao, Yan Chen, Shikai Zhang, Zhihui Zhang, Yongbing Cao, Dehua Yang, Ming-Wei Wang
Summary: This study comprehensively investigated the interactions between receptor activity-modulating proteins (RAMPs) and G protein-coupled receptors (GPCRs) using a bioluminescence resonance energy transfer (BRET) approach. The results revealed that RAMPs modulate the signal transduction of glucagon receptor family members in a receptor-specific manner. These findings provide new insights into the role of RAMPs in ligand recognition and receptor activation.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Multidisciplinary Sciences
Ewa Bielczyk-Maczynska, Meng Zhao, Peter-James H. Zushin, Theresia M. Schnurr, Hyun-Jung Kim, Jiehan Li, Pratima Nallagatla, Panjamaporn Sangwung, Chong Y. Park, Cameron Cornn, Andreas Stahl, Katrin J. Svensson, Joshua W. Knowles
Summary: This study identifies a rare genetic mutation associated with lower risk of type 2 diabetes and uncovers the role of Gpr151 in regulating hepatic glucose production in the liver.
NATURE COMMUNICATIONS
(2022)
Article
Endocrinology & Metabolism
Daniel Ocampo Daza, Christina A. Bergqvist, Dan Larhammar
Summary: This study provides a parsimonious explanation for the origin of the OTR/VTR gene family, based on phylogenetic and chromosomal conserved synteny analyses. The findings suggest a chromosome quadruplication event associated with whole-genome duplications early in vertebrate evolution, prior to the radiation of jawed vertebrates. The evolution of the OTR/VTR gene family can be explained by two whole-genome duplications followed by differential gene losses of VTR2 genes in different lineages.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Sergey A. Vishnivetskiy, Elizabeth K. Huh, Eugenia V. Gurevich, Vsevolod V. Gurevich
Summary: The finger loop in the central crest of arrestins plays a crucial role in sensing the activation state of receptors. Mutations in the finger loop residues significantly affect the binding of arrestin-1 to light-activated rhodopsin, highlighting the importance of the finger loop in recognizing the active receptor conformation. The data also suggest that arrestin-1 and its enhanced mutant bind various forms of rhodopsin differently.
JOURNAL OF NEUROCHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Joachim Neumann, Britt Hofmann, Stefan Dhein, Ulrich Gergs
Summary: Glucagon has various effects on the mammalian heart, including changes in contraction force, heart rate, and cardiac conduction system axis. The effects of glucagon on the heart differ depending on species, region, age, and concurrent disease. Glucagon is present in the mammalian heart and can act on cardiac glucagon receptors through autocrine or paracrine mechanisms.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Yulong Gong, Bingyuan Yang, Dingdong Zhang, Yue Zhang, Zihan Tang, Liu Yang, Katie C. Coate, Linlin Yin, Brittney A. Covington, Ravi S. Patel, Walter A. Siv, Katelyn Sellick, Matthew Shou, Wenhan Chang, E. Danielle Dean, Alvin C. Powers, Wenbiao Chen
Summary: Insufficient glucagon signalling leads to hyperaminoacidemia and stimulates the proliferation of glucagon-producing alpha cells. The study reveals that the amino acid sensitive calcium sensing receptor (CaSR) is necessary for alpha cell proliferation through Gq signalling during hyperaminoacidemia.
NATURE COMMUNICATIONS
(2023)
Article
Cell Biology
Jiayin Li, Peixuan Dang, Zhen Li, Tujing Zhao, Daojun Cheng, Dingyu Pan, Yufeng Yuan, Wei Song
Summary: This study reveals that Akh enhances carbohydrate production in the fat body and leads to hyperglycemia by phosphorylating ERK and translocating it to peroxisome via the CaMKII cascade. The findings demonstrate that the Akh/glucagon-peroxisomal-ERK axis is a key spatial regulator of glycemic control.
Article
Biochemistry & Molecular Biology
Emily Dean, Vikash Kumar, Ashleigh McConnell, Iohana B. Pagnoncelli, Chun Wu
Summary: This study investigated the activation mechanism of the delta-opioid receptor (DOR), identified key residues involved in the activation pathway, and provided essential information for experimental mutagenesis studies, facilitating the development of therapeutic agents targeting DOR.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Endocrinology & Metabolism
Peter Lindquist, Jakob S. Madsen, Hans Brauner-Osborne, Mette M. Rosenkilde, Alexander S. Hauser
Summary: This study analyzed missense variants in the human proglucagon gene GCG, identifying 184 unique variants that provided insights into the evolutionary constraint spectrum of proglucagon-derived peptides. The stereotypical peptides glucagon, GLP-1 and GLP-2 display fewer evolutionary alterations and are more likely to be functionally affected by genetic variation compared to other gene products.
FRONTIERS IN ENDOCRINOLOGY
(2021)
Review
Endocrinology & Metabolism
Yunbo Jia, Yang Liu, Linlin Feng, Siyu Sun, Guangwei Sun
Summary: This review summarizes the important roles of glucagon and its receptor in the development of diabetes, as well as recent research suggesting glucagon as a potential therapeutic target.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Zhao Yang, Jun-Yan Wang, Fan Yang, Kong-Kai Zhu, Guo-Peng Wang, Ying Guan, Shang-Lei Ning, Yan Lu, Yu Li, Chao Zhang, Yuan Zheng, Shu-Hua Zhou, Xin-Wen Wang, Ming-Wei Wang, Peng Xiao, Fan Yi, Cheng Zhang, Peng-Ju Zhang, Fei Xu, Bao-Hua Liu, Hua Zhang, Xiao Yu, Ning Gao, Jin-Peng Sun
Summary: This study reports the structure and function of GPR101, revealing its constitutive activity mechanism with Gs heterotrimer and identifying a side pocket for agonist screening. The functional experiments show that one agonist, AA-14, can partially restore the functions of the GH/IGF-1 axis and has rejuvenating effects. This study highlights the potential of targeting the orphan receptor GPR101 for rejuvenation.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Biology
Ioannis Galdadas, Shen Qu, Ana Sofia F. Oliveira, Edgar Olehnovics, Andrew R. Mack, Maria F. Mojica, Pratul K. Agarwal, Catherine L. Tooke, Francesco Luigi Gervasio, James Spencer, Robert A. Bonomo, Adrian J. Mulholland, Shozeb Haider
Summary: Understanding allosteric effects and communication pathways in enzymes through molecular dynamics simulations can provide insights into antibiotic resistance. Non-equilibrium simulations reveal long-distance communication pathways and cooperative loop dynamics as mechanisms for signal propagation. Clinical amino acid substitutions mapped onto identified pathways suggest a link between variation and allosteric behavior in important enzyme families.
Article
Multidisciplinary Sciences
Sten Ilmjaerv, Fabien Abdul, Silvia Acosta-Gutierrez, Carolina Estarellas, Ioannis Galdadas, Marina Casimir, Marco Alessandrini, Francesco Luigi Gervasio, Karl-Heinz Krause
Summary: The combination of G614 and L323 mutations in the Spike protein of SARS-CoV-2 creates a viral G/L variant that has replaced the initial D/P variant, with P323L mutation being crucial for the current variant's epidemiological success. While there is no significant correlation between COVID-19 mortality rates in different countries and the prevalence of Wuhan versus G/L variants, the G/L variant demonstrates major epidemiological supremacy over the original variant in terms of speed of emergence and ultimate predominance in individual countries.
SCIENTIFIC REPORTS
(2021)
Article
Polymer Science
Carlos Noble Jesus, Rhys Evans, Joe Forth, Carolina Estarellas, Francesco Luigi Gervasio, Giuseppe Battaglia
Summary: The study presents the design, simulation, synthesis, and reversible self-assembly of nanofibrils using polyhistidine-based oligopeptides. The inclusion of aromatic amino acids in the histidine block leads to the formation of amyloid-like fibrils with distinct antiparallel beta-strands. The structures undergo self-assembly in response to pH changes, offering potential for biotechnological and biomedical applications with pH-responsive fibrils in a physiologically relevant range.
Article
Biology
Ioannis Galdadas, Luca Carlino, Richard A. Ward, Samantha J. Hughes, Shozeb Haider, Francesco Luigi Gervasio
Summary: Mutations within the kinase domain of EGFR affect the equilibrium between its active and inactive conformations, leading to aberrant signaling in non-small cell lung cancer. The mutations cause a combination of effects including regulation of hinge motion, stabilization of dimeric interface, and local unfolding transitions.
Article
Infectious Diseases
Silvia Acosta-Gutierrez, Igor V. Bodrenko, Matteo Ceccarelli
Summary: The lack of new drugs for Gram-negative pathogens is a global threat to modern medicine. The study found that porins play a key role in cell uptake, aiding in a better understanding of the molecular descriptors behind whole-cell accumulation and molecular uptake in Gram-negative bacteria.
Article
Chemistry, Multidisciplinary
Susanta Haldar, Yashu Zhang, Ying Xia, Barira Islam, Sisi Liu, Francesco L. Gervasio, Adrian J. Mulholland, Zoe A. E. Waller, Dengguo Wei, Shozeb Haider
Summary: In this study, the mechanism of TMPyP4-induced RNA G-quadruplex (G4) unfolding was investigated using computational simulations and biophysical experiments. The results revealed that TMPyP4 interacts with RNA G4 through groove binding and top-face binding, disrupting hydrogen bonds between nucleotides.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Biochemistry & Molecular Biology
Sonia Di Gaetano, Luciano Pirone, Ioannis Galdadas, Serena Traboni, Alfonso Iadonisi, Emilia Pedone, Michele Saviano, Francesco Luigi Gervasio, Domenica Capasso
Summary: Galectins are soluble proteins involved in cancer progression and disease outcome, making them important targets for therapeutic intervention. Developing small inhibitors to selectively block galectin activity is a promising strategy for cancer therapy. This study designed a novel compound with high binding affinity to galectins and demonstrated its potential anticancer properties, paving the way for further development as an anticancer agent.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Dominykas Lukauskis, Marley L. Samways, Simone Aureli, Benjamin P. Cossins, Richard D. Taylor, Francesco Luigi Gervasio
Summary: Predicting the correct pose and binding affinity of a ligand to a protein is crucial in computer-aided drug discovery. OpenBPMD, an open-source Python reimplementation of BPMD, demonstrates performance matching or exceeding the original BPMD, and the combination with a grand-canonical Monte Carlo algorithm improves prediction accuracy.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Biology
Alberto Borsatto, Obaeda Akkad, Ioannis Galdadas, Shumeng Ma, Shymaa Damfo, Shozeb Haider, Frank Kozielski, Carolina Estarellas, Francesco Luigi Gervasio
Summary: Non-structural protein 1 (Nsp1) of SARS-CoV-2 is a main pathogenicity factor that suppresses host gene expression and innate immune response. This study identifies druggable pockets in Nsp1 and confirms their potential as targets for designing inhibitors. Targeting these pockets could disrupt the Nsp1-mRNA complex and provide a novel avenue for developing inhibitors against other Nsp1s in related coronaviruses.
Article
Chemistry, Medicinal
Jacqueline C. Calderon, Passainte Ibrahim, Dorothea Gobbo, Francesco Luigi Gervasio, Timothy Clark
Summary: We propose a metadynamics protocol to characterize the activation free-energy profiles of G-protein coupled receptors, focusing on the 5HT1A-receptor as a proof-of-principle study. By using the A100 activation index based on inter-helix distances, we perform metadynamics simulations and obtain free-energy profiles for the receptor in various complexes. Our results not only agree with previous experimental and computational data, but also provide detailed insights into the differences between active and inactive conformations and the role of microswitches in the activation mechanism.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Multidisciplinary Sciences
Arthur Radoux-Mergault, Lucie Oberhauser, Simone Aureli, Francesco Luigi Gervasio, Miriam Stoeber
Summary: Intracellular GPCRs, such as ORs, can be activated by permeant ligands in specific subcellular compartments, which has implications for agonist selectivity. This study examines the recruitment of signal transducers to mu-and delta-ORs in the Golgi apparatus and plasma membrane. The findings reveal differences in signaling effects and coupling selectivity between Golgi and plasma membrane ORs, suggesting that subcellular location plays a role in defining the effects of opioid drugs.
Article
Chemistry, Physical
Valerio Rizzi, Simone Aureli, Narjes Ansari, Francesco Luigi Gervasio
Summary: Enhanced sampling techniques, such as using collective variables (CVs) or parallel tempering, have greatly advanced molecular dynamics simulations for studying rare events and calculating free energy differences. We propose a replica exchange method called OneOPES that combines the advantages of multireplica simulations and CV-based enhanced sampling, providing an efficient and robust framework for complex systems.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Chemistry, Multidisciplinary
Vaibhav Kumar Shukla, Lucas Siemons, Francesco L. Gervasio, D. Flemming Hansen
Summary: This study demonstrates a strong correlation between the conformation of aromatic side chains near the active site and the opening and closing of functional loops of HDAC8. Mutations I19S-HDAC8 and S39E-HDAC8 were found to affect product release and substrate binding, providing insights into the mechanism of substantial downregulation caused by allosteric mutations.
Meeting Abstract
Biophysics
Silvia Acosta Gutierrez, Gabriele Marchello, Cesare De Pace, Gabriel Ing, Ciro Lopez Vazquez, Simona Pilotto, Finn Werner, Neil Wilkinson, Francesco L. Gervasio, Lorena Ruiz-Perez, Giuseppe Battaglia
BIOPHYSICAL JOURNAL
(2021)
Article
Chemistry, Multidisciplinary
Susanta Haldar, Yashu Zhang, Ying Xia, Barira Islam, Sisi Liu, Francesco L. Gervasio, Adrian J. Mulholland, Zoe A. E. Waller, Dengguo Wei, Shozeb Haider
Summary: The cationic porphyrin TMPyP4 can stabilize different topologies of DNA G4 structures via multiple binding modes, but can have both stabilizing and destabilizing effects on RNA G4 structures. The mechanism of TMPyP4-induced RNA G4 unfolding involves a two-state interaction mechanism with groove-bound and top-face-bound conformations. TMPyP4 disrupts Hoogsteen H-bonds between guanine bases and intercalates between the top-to-bottom G-tetrads, revealing a strong correlation between computational and experimental approaches.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
