Review
Biochemistry & Molecular Biology
Alexander O. Shpakov
Summary: Allosteric regulation plays a critical role in the functioning of GPCRs and their signaling pathways. The complexity of allosteric effects caused by various regulators determines the multiplicity and topology of allosteric sites in GPCRs. These sites are involved in the regulation of receptor activity, GPCR-complex formation, and endocytosis. They are also targets for synthetic allosteric regulators and modulators. The review provides an overview of the principles and mechanisms of GPCRs allosteric regulation, the diversity of allosteric sites, and the endogenous and synthetic allosteric regulators.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
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
Pharmacology & Pharmacy
Jyrki P. Kukkonen
Summary: Recent data indicates cooperative effects between identical orthosteric binding sites in a G-protein-coupled receptor dimer. A mathematical model was created to test this concept, showing that even a neutral receptor ligand can allosterically affect agonist binding through the orthosteric binding site.
PHARMACOLOGICAL RESEARCH
(2021)
Review
Biochemistry & Molecular Biology
Raudah Lazim, Donghyuk Suh, Jai Woo Lee, Thi Ngoc Lan Vu, Sanghee Yoon, Sun Choi
Summary: The presence of GPCR dimers has sparked research into their importance in disease pathogenesis and drug design, uncovering new signaling pathways and potential therapeutic targets. The increasing influence of computational methods in research is providing new avenues for understanding the functions and interactions of GPCRs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biology
Ramon Cierco Jimenez, Nil Casajuana-Martin, Adrian Garcia-Recio, Lidia Alcantara, Leonardo Pardo, Mercedes Campillo, Angel Gonzalez
Summary: The study analyzed 119,069 natural variants in human olfactory receptors, revealing a significant diversity of natural variations in the olfactory gene repertoire between individuals and populations, with a considerable number of changes occurring at the structurally conserved regions. Mutations in positions linked to the conserved GPCR activation mechanism were highlighted, which could imply phenotypic variation in olfactory perception.
Review
Endocrinology & Metabolism
Siyuan Shen, Chang Zhao, Chao Wu, Suyue Sun, Ziyan Li, Wei Yan, Zhenhua Shao
Summary: GPCRs, as the largest family of transmembrane proteins, regulate various physiological processes. However, their complicated signal transduction pathways and difficulties in drug development have presented challenges. By identifying new ligands that bind to allosteric sites, safer drugs for treating various diseases can be designed.
FRONTIERS IN ENDOCRINOLOGY
(2023)
Article
Multidisciplinary Sciences
Janik B. Hedderich, Margherita Persechino, Katharina Becker, Franziska M. Heydenreich, Torben Gutermuth, Michel Bouvier, Moritz Buenemann, Peter Kolb
Summary: Researchers computationally describe alternative allosteric pockets in G-protein-coupled receptors, identifying nine previously untargeted sites for synthetic ligands. They further investigate the potential of modulating receptor function through ligand binding to these sites.
NATURE COMMUNICATIONS
(2022)
Article
Pharmacology & Pharmacy
Sam Groom, Nina K. Blum, Alexandra E. Conibear, Alexander Disney, Rob Hill, Stephen M. Husbands, Yangmei Li, Lawrence Toll, Andrea Kliewer, Stefan Schulz, Graeme Henderson, Eamonn Kelly, Chris P. Bailey
Summary: This study confirmed that Compound 1 is a G protein-biased mu agonist that can induce substantial rapid receptor desensitisation in mammalian neurons. However, contrary to previous assumptions, the desensitisation effect of Compound 1 is dependent on G protein-coupled receptor kinase (GRK).
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Review
Endocrinology & Metabolism
Fraydoon Rastinejad
Summary: HNF4α is a crucial nuclear receptor that plays a significant role in the development and functioning of liver and pancreatic islet cells. It regulates vital metabolic processes and is associated with diabetes, metabolic disorders, and cancers. Its structure and functions have been extensively studied, revealing how different domains collaborate to achieve specific functions while forming cohesive higher-order architectures.
FRONTIERS IN ENDOCRINOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Sandra Berndt, Ines Liebscher
Summary: SFKs are crucial regulators of cell proliferation, differentiation, and survival, with their expression strongly linked to cancer development and tumor progression. The regulation of SFKs through GPCR-mediated pathways is complex and may involve direct protein interactions or allosteric regulation by arrestins and G proteins. The potential direct interaction between GPCRs and SFKs could lead to a novel mechanism of SFK signaling and identification of new GPCR-SFK interactions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Medicinal
Amanda E. Wakefield, David Bajusz, Dima Kozakov, Gyoergy M. Keseru, Sandor Vajda
Summary: Despite the limited number of GPCR structures cocrystallized with allosteric inhibitors, protein mapping has revealed the presence of druggable sites at the same locations in a large variety of GPCRs. These sites cluster at nine distinct locations and can be specifically targeted for allosteric modulation across GPCRs. The FTMap server facilitates protein mapping and is freely available for academic and governmental use.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Chemistry, Multidisciplinary
Longmei Li, Jin Zhang, Wenjing Sun, Weimin Gong, Changlin Tian, Pan Shi, Chaowei Shi
Summary: This study used F-19 solution NMR spectroscopy to investigate the conformational changes of G proteins upon interaction with detergent mimicking membrane and receptor. The results showed that there are two equilibrium states in the Gain apo states, and the interaction with detergents accelerates the conformational transformation.
CHINESE CHEMICAL LETTERS
(2022)
Article
Biochemistry & Molecular Biology
Jui-Hung H. Weng, Phillip T. Aoto, Robin Lorenz, Jian Wu, Sven Schmidt, Jascha Manschwetus, Pallavi Kaila-Sharma, Steve W. Silletti, Sebastian S. Mathea, Deep Chatterjee, Stefan Knapp, Friedrich Herberg, Susan Taylor
Summary: This study generated a comprehensive dynamic allosteric portrait of the C-terminal domains of LRRK2 using HDX-MS and MD simulations. It identified two helices that regulate LRRK2 conformation and function, providing potential sites for pharmacological intervention.
Article
Pharmacology & Pharmacy
Estefania Moreno, Nil Casajuana-Martin, Michael Coyle, Baruc Campos Campos, Ewa Galaj, Claudia Llinas del Torrent, Arta Seyedian, William Rea, Ning-Sheng Cai, Alessandro Bonifazi, Benjamin Floran, Zheng-Xiong Xi, Xavier Guitart, Vicent Casado, Amy H. Newman, Christopher Bishop, Leonardo Pardo, Sergi Ferre
Summary: This study provides evidence that heteromerization of G protein-coupled receptors (GPCRs), specifically dopamine D1 and D3 receptors, can influence the pharmacological properties of selective ligands. In vivo experiments support the involvement of D1R-D3R heteromers in the development of L-DOPA-induced dyskinesia in Parkinson's disease, suggesting the potential of targeting GPCR heteromers for drug development.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Nicole Ahrens, Dana Elbers, Helena Greb, Ulrike Janssen-Bienhold, Karl-Wilhelm Koch
Summary: The study revealed diverse properties of recoverin and opsin kinase in zebrafish retina due to differential expression and interaction profiles, indicating distinct roles of different recoverin paralogs in rod and cone cells.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Barry J. Grant, Lars Skjaerven, Xin-Qiu Yao
Summary: Bio3D is a set of R packages for analyzing biomolecular sequences, structures, and dynamics, with recent developments including segregation into separate packages and introduction of a new method called ensemble difference distance matrix analysis (eDDM). The eDDM approach helps identify residue-wise determinants underlying specific functional processes by calculating and comparing atomic distance matrices across large sets of homologous structures.
Article
Chemistry, Medicinal
Rachel A. Rowlands, Qiuyan Chen, Renee A. Bouley, Larisa Avramova, John J. G. Tesmer, Andrew D. White
Summary: The ability of GRK2 and GRK5 to regulate GPCR desensitization makes them attractive targets for heart failure and cancer treatment. Previous research showed potential for selective inhibition of GRK5 over GRK2 using a specific residue, but the inhibitors were not very potent. A new study successfully adapted an indolinone scaffold with covalent warheads, creating compounds with high selectivity for GRK5 and low nanomolar potency.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Jacques Kumutima, Xin-Qiu Yao, Donald Hamelberg
Summary: The multifunctional protein p53 functions as the central molecular sensor of cellular stresses and plays a role in regulating cell death processes, including apoptosis and necrosis. Our computational investigation identified the specific binding site of cyclophilin D on p53 at proline 151 and characterized how cyclophilin D catalyzes peptide bond isomerization to regulate p53 activity. The isomerization induced dynamical changes in both local and distal regions, suggesting an allosteric effect involved in the interaction between p53 and cyclophilin D.
Article
Chemistry, Physical
Thomas Dodd, Xin-Qiu Yao, Donald Hamelberg, Ivaylo Ivanov
Summary: In this study, a new method called SOAN is developed for finding critical residues in protein structural or dynamical networks through suboptimal path analysis, which outperforms existing software packages in terms of speed and accuracy, thus enhancing computational efficiency.
Article
Biochemistry & Molecular Biology
M. Claire Cato, Yu-Chen Yen, Charnelle J. Francis, Kaely E. Elkins, Afzaal Shareef, Rachel Sterne-Marr, John J. G. Tesmer
Summary: This paper discusses three distinct models for how GRKs recognize activated GPCRs, addresses limitations in the approaches used to generate them, and experimentally tests a hypothetical GPCR interaction site in GRK2 suggested by the two newest models.
Article
Chemistry, Multidisciplinary
Xiaonan Deng, Xin-Qiu Yao, Ken Berglund, Bin Dong, Daniel Ouedraogo, Mohammad A. Ghane, You Zhuo, Cheyenne McBean, Zheng Zachory Wei, Samer Gozem, Shan P. Yu, Ling Wei, Ning Fang, Angela M. Mabb, Giovanni Gadda, Donald Hamelberg, Jenny J. Yang
Summary: The study introduces a novel ER-targeted calcium indicator, R-CatchER, with superior kinetics in various cell types, revealing the spatiotemporal dynamics and functional cooperativity of ER Ca2+ and proposing a design principle for genetically encoded Ca2+ indicators.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Multidisciplinary Sciences
Qiuyan Chen, Manolo Plasencia, Zhuang Li, Somnath Mukherjee, Dhabaleswar Patra, Chun-Liang Chen, Thomas Klose, Xin-Qiu Yao, Anthony A. Kossiakoff, Leifu Chang, Philip C. Andrews, John J. G. Tesmer
Summary: GRKs selectively phosphorylate activated GPCRs for desensitization, with a conserved region at the GRK N terminus playing a crucial role. Cryo-EM reconstructions revealed the binding mechanism between GRK1 and Rho*, providing insights into how a small family of protein kinases can recognize and be activated by numerous GPCRs.
Article
Chemistry, Physical
Xin-Qu Yao, Donald Hamelberg
Summary: Allosteric regulation is important for coordinating cellular processes, and a flexible biomolecule is necessary for allosteric communication. This study introduces a computational method to identify allosteric communication pathways and key residues by considering conformational changes. The method was applied to study imidazole glycerol phosphate synthase (IGPS), and it was found that considering conformational changes is crucial for capturing important allosteric residues. Furthermore, the study revealed that different binding processes generally use a similar group of residues in defining allosteric communication pathways. The strength of effector binding also affects the fine-tuning of allosteric coupling. The results are robust against parameter variations and network construction details.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Chemistry, Physical
Xin-Qiu Yao, Donald Hamelberg
Summary: Conformational dynamics of proteins play a crucial role in their biological processes and functional regulation. This Perspective explores the description of allosteric regulation through protein dynamical responses and introduces alternative computational approaches to map allosteric communication pathways at the atomic level.
JOURNAL OF PHYSICAL CHEMISTRY B
(2022)
Article
Multidisciplinary Sciences
Yu-Chen Yen, Christopher T. Schafer, Martin Gustaysson, Stefanie A. Eberle, Pawel K. Dominik, Dawid Deneka, Penglie Zhang, Thomas J. Schall, Anthony A. Kossiakoff, John J. G. Tesmer, Tracy M. Handel
Summary: This study presents cryo-EM structures of ACKR3 in complex with CXCL12, a more potent CXCL12 variant, and a small-molecule agonist. The binding poses of these chemokines are different from those established for CXCR4 and observed in other receptor-chemokine complexes. These structures, together with functional studies, provide insights into the ligand-binding promiscuity of ACKR3, its inability to couple to G proteins, and its bias towards beta-arrestin, laying the foundation for understanding the physiological interplay of ACKR3 with other GPCRs.
Article
Chemistry, Physical
Jacques Kumutima, Xin-Qiu Yao, Donald Hamelberg
Summary: This study investigates the catalytic mechanism of unmodified and modified CypD using molecular dynamics simulations and analyzes the conformational dynamics. The results show that both unmodified and modified CypD lower the isomerization free energy barrier, supporting their catalytic activity. The phosphorylation and acetylation modifications have different effects on CypD's catalytic activity, which is due to significant conformational changes in different functional states.
JOURNAL OF PHYSICAL CHEMISTRY B
(2022)
Article
Biochemistry & Molecular Biology
Daniel Ouedraogo, Michael Souffrant, Xin-Qiu Yao, Donald Hamelberg, Giovanni Gadda
Summary: Numerous studies have shown that enzymes have multiple conformational changes during catalysis. In this study, the effect of a mutation (I335H) on the catalytic function of PaDADH was investigated using molecular dynamics and biochemical techniques. The results revealed that the mutation led to a more closed conformation in PaDADH.
Article
Chemistry, Medicinal
Michael Souffrant, Xin-Qiu Yao, Donald Hamelberg
Summary: Drug resistance in antiviral treatments is a serious issue in public health. Viral proteins mutate fast, allowing them to escape drugs while still being viable. The mechanism of drug resistance in HIV-1 protease is unclear, but studying conformational ensembles can help detect functional changes.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Chemistry, Physical
Furyal Ahmed, Xin-Qiu Yao, Donald Hamelberg
Summary: This study compares the conformational dynamics of cyclophilin isoforms and identifies key dynamic residues in the gatekeeper 2 region that are essential for their catalytic activity. The highly conserved glycine residue (Gly80) is predicted to contribute to the local flexibility, which is further confirmed by molecular dynamics simulations on mutants (G80A) of CypE and CypA. The mutations lead to changes in flexibility and catalytic behavior of CypE and CypA, suggesting a loss of function.
JOURNAL OF PHYSICAL CHEMISTRY B
(2023)
Article
Biochemistry & Molecular Biology
Jessica J. Waninger, Tyler S. Beyett, Varun V. Gadkari, Ronald F. Siebenaler, Carson Kenum, Sunita Shankar, Brandon T. Ruotolo, Arul M. Chinnaiyan, John J. G. Tesmer
Summary: Oncogenic mutations in the KRAS gene result in a constitutively active form, making direct targeting of KRAS challenging. A study identified AGO2 as a protein that interacts with RAS-driven oncogenesis. While purified AGO2 was shown to co-immunoprecipitate with KRAS, the complex between FL AGO2 and KRAS could not be isolated, indicating further research is needed to understand the interaction of KRAS with purified AGO2 forms.
BIOCHEMISTRY AND BIOPHYSICS REPORTS
(2022)