Article
Chemistry, Multidisciplinary
Prashant Donthamsetti, David B. Konrad, Belinda Hetzler, Zhu Fu, Dirk Trauner, Ehud Y. Isacoff
Summary: G protein-coupled receptors (GPCRs) are common drug discovery targets, but the complexity of in vivo receptor activation has hindered drug development. Photopharmacology offers the potential to control drug action using light. Recent advances include a photoswitchable allosteric agonist that selectively activates receptors.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Multidisciplinary Sciences
Hiroaki Akasaka, Tatsuki Tanaka, Fumiya K. Sano, Yuma Matsuzaki, Wataru Shihoya, Osamu Nureki
Summary: LPA(1) is a GPCR that is a drug target for various diseases. The authors reported a cryo-EM structure of the active human LPA(1)-G(i) complex bound to a more potent LPA analog against LPA(1) and clarified the ligand recognition mechanism.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Quinton M. Dowling, Hannah E. Volkman, Elizabeth E. Gray, Sergey Ovchinnikov, Stephanie Cambier, Asim K. Bera, Banumathi Sankaran, Max R. Johnson, Matthew J. Bick, Alex Kang, Daniel B. Stetson, Neil P. King
Summary: Cyclic GMP-AMP synthase (cGAS) is an important pattern recognition receptor involved in the innate immune response. By binding to dsDNA, cGAS is activated to produce cGAMP, which triggers a strong interferon response. Researchers have successfully designed constitutively active cGAS variants that can function independently of dsDNA. These variants showed therapeutic activity in tumor regression when expressed in tumor cells. This study provides insights into enzyme stabilization and offers potential applications in understanding inflammatory diseases.
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Yiqun Yu, Zhenjie Ma, Jody Pacalon, Lun Xu, Weihao Li, Christine Belloir, Jeremie Topin, Loic Briand, Jerome Golebiowski, Xiaojing Cong
Summary: In this study, the critical role of the OR extracellular loop 2 (ECL2) in the promiscuity and specificity of olfactory receptors (ORs) was demonstrated. Molecular modeling and site-directed mutagenesis were used to construct 3D OR models, which revealed that ECL2 controls the shape and volume of the odorant-binding pocket. Furthermore, virtual screening using these models showed a high hit rate for new OR agonists and antagonists.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Sweta Adhikary, Omar Koita, Joseph J. Lebowitz, William T. Birdsong, John T. Williams
Summary: This study suggests that chronic opioid treatment alters kinase regulation of nonopioid GPCRs, highlighting the importance of sustained opioid receptor signaling in initiating adaptive processes downstream.
MOLECULAR PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Bharathi, Kuldeep K. Roy
Summary: This study elucidated the three-dimensional structure and conformational dynamics of GPR3 complexed with the inverse agonist AF64394. Multiple hydrogen bonds and hydrophobic interactions were predicted, and the inactive state of GPR3 was revealed during molecular dynamics simulations.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Biochemistry & Molecular Biology
Seung-Hee Choi, Munkhzaya Byambaragchaa, Dae-Jung Kim, Jong-Hyuk Lee, Myung-Hwa Kang, Kwan-Sik Min
Summary: We studied the signal transduction mechanism using inactivating and activating mutants of luteinizing hormone receptor (LHR) in eels. The activating mutant (D576G) showed a significant increase in basal cAMP response, while the inactivating mutant (R476H) completely lost the ability to respond to cAMP. The mutants also exhibited different rates of loss in cell-surface expression compared to the wild type LHR. These findings provide important insights into the structure-function relationship of LHR-LH complexes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Marin Matic, Pasquale Miglionico, Manae Tatsumi, Asuka Inoue, Francesco Raimondi
Summary: Selective formation of GPCR-G protein complexes is crucial for regulating signal transduction. By using a data-driven approach, the authors demonstrate that the structures of experimental and predicted complex interfaces provide information on G protein binding preferences. GPCRs are key regulators of cell signaling, transducing extracellular stimuli into the cell through selective coupling to intracellular G proteins. The authors conduct a computational analysis to investigate the structural determinants of G protein coupling in experimental and predicted 3D GPCR-G protein complexes.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Argha Mitra, Arijit Sarkar, Marton Richard Szabo, Attila Borics
Summary: Recent advancements in experimental structural biology have provided high-resolution structures of G protein-coupled receptors, shedding light on the mechanisms of transition between active and inactive states. Molecular dynamics simulations demonstrate that external stimulus transmission to the intracellular surface of the receptor involves subtle movements of polar amino acid side chains.
Article
Multidisciplinary Sciences
Anne-Marinette Cao, Robert B. Quast, Fataneh Fatemi, Philippe Rondard, Jean-Philippe Pin, Emmanuel Margeat
Summary: The study utilized smFRET to investigate the structural dynamics of metabotropic glutamate receptor mGlu2 and found that positive allosteric modulators or the Gi protein can stabilize mGlu2 in the active state, leading to full receptor activation. This discovery provides important insights into the role of allosteric modulators in mGlu activation.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Aline Chessel, Noemie De Croze, Maria Dolores Molina, Laura Taberner, Philippe Dru, Luc Martin, Thierry Lepage
Summary: During early development of the sea urchin embryo, ERK signalling is activated in mesodermal precursors through a cell-autonomous mechanism involving the transcriptional activation of the gene encoding KSR3. KSR3 is an allosteric activator of RAF and can activate ERK signalling independently of RAS in non-chordate metazoa. The findings provide insights into the evolution and co-option of the ERK signalling pathway.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Andrew B. Kleist, Shawn Jenjak, Andrija Sente, Lauren J. Laskowski, Martyna Szpakowska, Maggie M. Calkins, Emilie Anderson, Lisa M. McNally, Raimond Heukers, Vladimir Bobkov, Francis C. Peterson, Monica A. Thomas, Andy Chevigne, Martine J. Smit, John D. McCorvy, M. Madan Babu, Brian F. Volkman
Summary: NMR experiments on ACKR3 revealed that the recruitment of beta-arrestins is associated with conformational exchange at key regions of the receptor, and identified an allosteric hub in the core receptor that coordinates transitions among different conformational states, guiding beta-arrestin recruitment.
Article
Biochemistry & Molecular Biology
Kevin M. Knight, Soumadwip Ghosh, Sharon L. Campbell, Tyler J. Lefevre, Reid H. J. Olsen, Alan Smrcka, Natalie H. Valentin, Guowei Yin, Nagarajan Vaidehi, Henrik G. Dohlman
Summary: Proteins are crucial in signal transduction and pharmacology, with G proteins playing a central role. Research has shown that a conserved network of amino acids dictates the release of G protein subunits, providing insights into the molecular basis of G protein activation.
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
Biochemistry & Molecular Biology
Hannes Schihada, Rawan Shekhani, Gunnar Schulte
Summary: The research team developed and validated eight G protein sensors that can measure the activity of all major families of G proteins, along with a protocol to identify constitutive GPCR or G protein signaling in live cells.
Article
Agriculture, Dairy & Animal Science
H. -J. Zhang, Z. -H. Cui, M. Liu, T. -Q. Min, X. Xiao, Z. -Q. Wang, Y. -X. Tao
Summary: The study investigated three naturally occurring mutations in chicken MC3R and found significant defects in receptor pharmacology for G104S and L151R, while the mechanism of action for M54L remains to be further explored.
DOMESTIC ANIMAL ENDOCRINOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Li-Kun Yang, Zhi-Shuai Hou, Ya-Xiong Tao
Summary: GPCRs are crucial in transmitting extracellular signals and regulating physiological functions. Mutations in GPCRs can lead to diseases and studying biased agonism provides insights into disease pathogenesis.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2021)
Article
Biochemistry & Molecular Biology
Ren-Lei Ji, Ya-Xiong Tao
Summary: Two new human MRAP2 splice variants were identified in this study, and the effects of MRAP1 and MRAP2 on MC3R and MC4R were investigated. The results suggest that MRAPs play important roles in the signaling and regulation of neural MC3R and MC4R.
Article
Chemistry, Medicinal
Luis E. Gimenez, Terry A. Noblin, Savannah Y. Williams, Satarupa Mullick Bagchi, Ren-Lei Ji, Ya-Xiong Tao, Claus B. Jeppesen, Kilian W. Conde-Frieboes, Tomi K. Sawyer, Paolo Grieco, Roger D. Cone
Summary: Peptides containing DNal(2 ')7, reported as MC3R subtype-specific agonists, were found to lack MC3R agonist activity. The cell lines used for pharmacological characterization were mischaracterized in terms of receptor subtype expression. Furthermore, peptides containing DNal(2 ')7 primarily exhibit antagonism of MC3R and MC4R.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Endocrinology & Metabolism
Huifei Sophia Zheng, Jeffrey G. Daniel, Julia M. Salamat, Laci Mackay, Chad D. Foradori, Robert J. Kemppainen, Satyanarayana R. Pondugula, Ya-Xiong Tao, Chen-Che Jeff Huang
Summary: This study investigated the early transcriptomic responses to dexamethasone (Dex) stimulation in vitro and in vivo, showing that there were distinct differences in the gene expression patterns. The adrenal glands of mice treated with Dex for 1 hour showed a strong association with the development of neuronal cells, indicating a rapid response to Dex in the adrenal medulla. However, in the Y-1 cell line, only a small proportion of genes exhibited differential expression after 1 hour of Dex treatment, and their expression returned to basal levels after 24 hours.
ENDOCRINE CONNECTIONS
(2022)
Review
Biochemistry & Molecular Biology
Li-Qin Ji, Ye Hong, Ya-Xiong Tao
Summary: MC5R is a unique melanocortin receptor with distinct tissue expression patterns, pharmacological properties, and physiological functions. It is widely distributed in both the central nervous system and peripheral tissues and is associated with lipid production, sexual behavior, immunomodulation, and energy metabolism.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Endocrinology & Metabolism
Alfredo Ulloa-Aguirre, Teresa Zarinan, Ruben Gutierrez-Sagal, Ya-Xiong Tao
Summary: This article discusses the folding and trafficking of GPCRs involved in endocrine diseases, as well as experimental approaches to correct their misfolding, with a particular focus on the promising use of pharmacological chaperones.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Xiao-Chen Yuan, Ya-Xiong Tao
Summary: The discovery of melanocortins and their receptors has led to extensive research over the past 100 years, with particular focus on the neural melanocortin receptors' role in regulating energy homeostasis and potential therapeutic applications for treating metabolic conditions.
Article
Biochemistry & Molecular Biology
Ren-Lei Ji, Shan-Shan Jiang, Ya-Xiong Tao
Summary: The neural melanocortin receptors (MCRs) and their accessory proteins MRAP1 and MRAP2 play crucial roles in regulating energy homeostasis. This study reveals that MRAP1 and MRAP2s have species-specific effects on canine neural MCRs, providing a better understanding of their regulation.
Article
Endocrinology & Metabolism
Li-Qin Ji, Ying-Zhu Rao, Yong Zhang, Rong Chen, Ya-Xiong Tao
Summary: In this study, the orange-spotted grouper's Mc5r gene was cloned and its pharmacological characteristics were investigated. Four ligands were found to bind to Mc5r, increasing intracellular cAMP levels. Mrap2 was found to regulate the surface expression and activity of Mc5r. This study provides new insights into the pharmacology and regulation of fish Mc5r.
GENERAL AND COMPARATIVE ENDOCRINOLOGY
(2023)
Editorial Material
Endocrinology & Metabolism
Xiao-Chen Yuan, Ya-Xiong Tao
FRONTIERS IN ENDOCRINOLOGY
(2023)
Article
Agriculture, Dairy & Animal Science
Yang Li, Wei-Jia Song, Shao-Kui Yi, Hui-Xia Yu, Hao-Lin Mo, Ming-Xing Yao, Ya-Xiong Tao, Li-Xin Wang
Summary: This study cloned and characterized the GPR84 gene in grass carp and found that it is responsive to medium-chain fatty acids and DIM. The expression of GPR84 in grass carp is high in the liver and spleen.
Article
Biochemistry & Molecular Biology
Ren-Lei Ji, Ting Liu, Zhi-Shuai Hou, Hai-Shen Wen, Ya-Xiong Tao
Summary: Four mc4r genes were identified in rainbow trout, which are homologous to those of other fish and mammals. These genes have undergone different evolutionary processes. This study provides the foundation for future research on the physiological functions of mc4r paralogs and the evolution of mc4r in vertebrates.
Editorial Material
Multidisciplinary Sciences
Chao Zhang, Ya-Xiong Tao
Article
Chemistry, Medicinal
Kenneth A. Gruber, Ren-Lai Ji, Fabio Gallazzi, Shaokai Jiang, Steven R. Van Doren, Ya-Xiong Tao, Jessica Newton Northup
Summary: During the development of a drug for treating cachexia, we discovered the importance of peptide transport across the blood-brain barrier. Through screening the medical literature, we found that bile salt transport peptides could effectively cross the BBB. We designed a drug peptide, TCMCB07, and made modifications to its C-terminal amino acid sequence to extend its half-life, providing a platform approach for producing similar drug peptides.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2022)