Article
Pharmacology & Pharmacy
Lyndsay R. Watkins, Cesare Orlandi
Summary: Members of the GPCR family, including many less-studied orphan receptors, play important physiological roles and serve as attractive drug targets. A novel approach has been developed to detect G protein coupling in unliganded orphan GPCRs, shedding light on the pathophysiological processes associated with certain orphan receptors. This platform provides a valuable tool for ongoing studies in orphan receptor signalling and de-orphanization efforts.
BRITISH JOURNAL OF PHARMACOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Manuel Grundmann, Eckhard Bender, Jens Schamberger, Frank Eitner
Summary: The physiological function of free fatty acids has been redefined with the discovery that they can also act as signaling molecules at FFA receptors. Researchers are exploring allosteric ligands targeting FFARs to develop drugs for various diseases, aiming to leverage the potential of GPCRs in drug discovery.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Neurosciences
Ruth C. Werthmann, Manuel Tzouros, Jens Lamerz, Angelique Augustin, Thorsten Fritzius, Luca Trovo, Michal Stawarski, Adi Raveh, Catherine Diener, Christophe Fischer, Martin Gassmann, Lothar Lindemann, Bernhard Bettler
Summary: Recent studies have shown that mGlu1 and mGlu5 form functional heterodimers in the brain, exhibiting symmetric signal transduction where both protomers need to reach an active conformation for full receptor activity. This highlights differences in the signaling transduction of heterodimeric mGluRs that influence allosteric modulation.
Review
Pharmacology & Pharmacy
Ilana B. Kotliar, Emily Lorenzen, Jochen M. Schwenk, Debbie L. Hay, Thomas P. Sakmar
Summary: G protein-coupled receptors (GPCRs) interact with a variety of membrane proteins, but the extent and mechanisms of these interactions are not well understood. RAMPs, a class of GPCR-interacting proteins, have been extensively studied. Recent research suggests that GPCR-RAMP interactions may be more widespread than previously thought. This review summarizes the latest techniques for discovering GPCR-RAMP interactions and their functional consequences, and discusses future research prospects.
PHARMACOLOGICAL REVIEWS
(2023)
Article
Biochemistry & Molecular Biology
Erica R. R. Hendrikse, Tayla A. A. Rees, Zoe Tasma, Michael L. L. Garelja, Andrew Siow, Paul W. R. Harris, John B. B. Pawlak, Kathleen M. M. Caron, Elizabeth S. S. Blakeney, Andrew F. F. Russo, Levi P. P. Sowers, Thomas A. A. Lutz, Christelle Le Foll, Christopher S. S. Walker, Debbie L. L. Hay
Summary: This study evaluated antibodies for the detection of RAMP1 protein and found that two antibodies could detect a RAMP1-like band in rodent brain tissue, but with cross-reactivity to other proteins. The anatomical localization of RAMP1 in the brain could not be determined, highlighting the need for comprehensive validation of RAMP1 antibodies. This research has broader implications for GPCR/ligand pairings beyond the field of CGRP.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Mengrong Li, Yiqiong Bao, Ran Xu, Miaomiao Li, Lili Xi, Jingjing Guo
Summary: The identification and development of non-peptide allosteric modulators for PTH1R have gained attention. It has been found that a negative allosteric modulator (NAM) inhibits the activation of PTH1R, but the mechanism is unclear. Molecular dynamics simulations and analytical approaches reveal that NAM destabilizes the PTH1R-PTH-spep/qpep complexes, weakens PTH/peps-PTH1R binding, and reduces intra- and inter-molecular couplings in PTH1R. Compared with positive allosteric effects induced by extracellular Ca2+, the negative allosteric regulator significantly reduces the correlation between PTH and G-protein binding sites. These findings contribute to the development of new therapeutics for diseases caused by PTH1R abnormal activation.
Article
Chemistry, Physical
Riccardo Aguti, Mattia Bernetti, Stefano Bosio, Sergio Decherchi, Andrea Cavalli
Summary: Allostery is a crucial feature of biomolecular systems, impacting their functioning through intricate interplays between residues and protein structures. Computational approaches for correlation estimation provide insights into these complexes but can lead to different conclusions and outcomes. This article compares three computational methods on pharmaceutical targets, revealing consensus in some aspects but also highlighting the importance of different notions in identifying specific pockets and communications.
JOURNAL OF CHEMICAL PHYSICS
(2023)
Article
Chemistry, Medicinal
Zira T. K. Gannam, Haya Jamali, Oh Sang Kweon, James Herrington, Shanelle R. Shillingford, Christina Papini, Erik Gentzel, Elias Lolis, Anton M. Bennett, Jonathan A. Ellman, Karen S. Anderson
Summary: This study explores the structure-activity relationship of a class of MKP5 inhibitors and designs and synthesizes a series of derivative compounds for evaluation of MKP5 inhibition. The crystal structures of enzyme-inhibitor complexes are further analyzed to elucidate the necessary requirements for MKP5 inhibition. The results lay the foundation for the development of more potent MKP5 allosteric inhibitors for the treatment of dystrophic muscle disease.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Ilana B. Kotliar, Emilie Ceraudo, Kevin Kemelmakher-Liben, Deena A. Oren, Emily Lorenzen, Tea Dodig-Crnkovic, Mizuho Horioka-Duplix, Thomas Huber, Jochen M. Schwenk, Thomas P. Sakmar
Summary: The interaction between MRGPRX4 and RAMP2 can regulate the signaling pathway and cell surface expression of cholestatic itch, suggesting potential therapeutic implications for future drug development in treating cholestatic itch.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Geng Chen, Jun Xu, Asuka Inoue, Maximilian F. Schmidt, Chen Bai, Qiuyuan Lu, Peter Gmeiner, Zheng Liu, Yang Du
Summary: This study reports two structures of the human GPR88-Gi complex, revealing an allosteric ligand involved in the interaction between the receptor and G-protein, and a potential endogenous ligand of GPR88.
NATURE COMMUNICATIONS
(2022)
Article
Pharmacology & Pharmacy
Kequan Fu, Wenbing Chen, Mingzhu Meng, Huimin Zhao, Haoxing Yuan, Yinan Wang, Ying Ren, Yi Yun, Dong Guo
Summary: The adenosine A1 receptor is an important target for metabolic disorders and plays a significant role in regulating free fatty acid levels. This study examined the effect of an allosteric modulator on the action of an A1 receptor agonist in regulating lipolysis. The results showed that the allosteric modulator enhanced the antilipolytic action of the agonist by slowing down its dissociation from the receptor and downregulating the cAMP/HSL pathway. This study highlights the potential application of A1 receptor allosteric modulators in the treatment of metabolic diseases.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2023)
Article
Immunology
Alexander P. Young, Eileen M. Denovan-Wright
Summary: Microglia, resident immune cells of the brain, can be modulated through the activation of cannabinoid receptors to reduce their pro-inflammatory activity and decrease secondary neuronal damage.
BRAIN BEHAVIOR AND IMMUNITY
(2022)
Article
Biochemistry & Molecular Biology
Xin Lin, Nicole M. Fisher, Shalini Dogra, Rebecca K. Senter, Carson W. Reed, Jacob J. Kalbfleisch, Craig W. Lindsley, Wesley B. Asher, Zixiu Xiang, Colleen M. Niswender, Jonathan A. Javitch
Summary: The activity of hippocampal SC-CA1 synapses is regulated by mGlu(7/8) heterodimers, and different mGlu(7) NAM compounds exhibit varying activity on these heterodimers.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Sophie Shi, Solene N. Lefebvre, Laurie Peverini, Adrien H. Cerdan, Paula Milan Rodriguez, Marc Gielen, Jean-Pierre Changeux, Marco Cecchini, Pierre-Jean Corringer
Summary: This study investigates the gating mechanism of the glycine receptor through voltage-clamp fluorometry (VCF). Fluorescence reports a glycine-induced conformational change that occurs before pore opening. Molecular dynamic simulations show the dynamic nature of a partial agonist bound-closed Cryo-EM structure, generating docking properties that recapitulate the VCF data. This research reveals the progressive propagating transition towards channel opening and highlights the structural plasticity within the mechanism of action of allosteric effectors.
NATURE COMMUNICATIONS
(2023)
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)
Review
Pharmacology & Pharmacy
Tayla A. Rees, Erica R. Hendrikse, Debbie L. Hay, Christopher S. Walker
Summary: In addition to CGRP, calcitonin family peptides may be therapeutically useful in treating migraines and other pain disorders. Their localization in peripheral pain pathways could play a role in migraines and pain.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Review
Pharmacology & Pharmacy
Michael L. Garelja, Christopher S. Walker, Debbie L. Hay
Summary: The development of drugs targeting the CGRP system has been a major breakthrough in migraine management. These drugs can be classified into antibodies and receptor antagonists, with receptor antagonists further divided into small molecule antagonists and antibody antagonists. While antagonists are most potent at the CGRP receptor, they may also show antagonism at the AMY(1) receptor, indicating the need for further research.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Michael L. Garelja, Rebekah L. Bower, Margaret A. Brimble, Shanan Chand, Paul W. R. Harris, Muhammad Aqfan Jamaluddin, Jakeb Petersen, Andrew Siow, Christopher S. Walker, Debbie L. Hay
Summary: The pharmacology of the mouse CLR/CTR and RAMPs receptors differs from that of humans, with mouse receptors showing reduced discrimination between ligands, posing challenges for interpreting data in preclinical models and translating findings from mice to humans. New ligands are needed to differentiate between these complexes.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Brian P. Cary, Giuseppe Deganutti, Peishen Zhao, Tin T. Truong, Sarah J. Piper, Xinyu Liu, Matthew J. Belousoff, Radostin Danev, Patrick M. Sexton, Denise Wootten, Samuel H. Gellman
Summary: Recent advances in understanding the structures of G-protein-coupled receptors (GPCRs) have highlighted the importance of conformational flexibility in signal propagation. By studying the activation of the GLP-1 receptor, it was found that the conformational plasticity of peptide agonists plays a crucial role in determining agonist efficacy.
NATURE CHEMICAL BIOLOGY
(2022)
Article
Pharmacology & Pharmacy
Peishen Zhao, Tin T. Truong, Jon Merlin, Patrick M. Sexton, Denise Wootten
Summary: This study investigates the kinetics of GLP-1R activation and cAMP production mediated by peptide agonists. The results reveal a positive correlation between peptide agonist dissociation kinetics and the onset, duration, and conformational change of receptor-G protein coupling and cAMP signaling. These findings advance the understanding of molecular events that link GLP-1R ligand binding to intracellular signaling and have implications for the agonist action at other related class B1 GPCRs.
BIOCHEMICAL PHARMACOLOGY
(2022)
Article
Pharmacology & Pharmacy
Juliana E. Milburn, Kaleeckal G. Harikumar, Sarah J. Piper, Sweta Raval, Arthur Christopoulos, Denise Wootten, Patrick M. Sexton, Laurence J. Miller
Summary: This study provides a deeper understanding of the activation mechanisms of class B1 G protein-coupled receptors. The interaction between the amino-terminal region of secretin and the seventh transmembrane segment of its receptor plays a structurally specific role, and a charge-charge interaction helps to drive functional activation.
MOLECULAR PHARMACOLOGY
(2022)
Review
Endocrinology & Metabolism
Brian P. Cary, Xin Zhang, Jianjun Cao, Rachel M. Johnson, Sarah J. Piper, Elliot J. Gerrard, Denise Wootten, Patrick M. Sexton
Summary: G protein-coupled receptors (GPCRs), particularly the B1 class, play a critical role in maintaining homeostasis and are important drug targets. Recent advances in cryo-electron microscopy have provided valuable insights into the structure and dynamics of these receptors, which contribute to our understanding of their functions.
Editorial Material
Biochemistry & Molecular Biology
Tayla A. A. Rees, Debbie L. L. Hay, Christopher S. S. Walker
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Pharmacology & Pharmacy
Ilana B. Kotliar, Emily Lorenzen, Jochen M. Schwenk, Debbie L. Hay, Thomas P. Sakmar
Summary: G protein-coupled receptors (GPCRs) interact with a variety of membrane proteins, but the extent and mechanisms of these interactions are not well understood. RAMPs, a class of GPCR-interacting proteins, have been extensively studied. Recent research suggests that GPCR-RAMP interactions may be more widespread than previously thought. This review summarizes the latest techniques for discovering GPCR-RAMP interactions and their functional consequences, and discusses future research prospects.
PHARMACOLOGICAL REVIEWS
(2023)
Review
Physiology
Andrew F. Russo, Debbie L. Hay
Summary: Calcitonin gene-related peptide (CGRP) is a neuropeptide with diverse physiological functions. It acts through various receptors and is associated with disease states such as migraine. Therapeutics targeting the CGRP axis have shown success in bench-to-bedside translation. This review provides a comprehensive overview of CGRP's regulation, expression, physiological actions, and potential therapeutic targeting in various systems and diseases.
PHYSIOLOGICAL REVIEWS
(2023)
Correction
Biochemistry & Molecular Biology
Alexander S. Powers, Vi Pham, Wessel A. C. Burger, Geoff Thompson, Yianni Laloudakis, Nicholas W. Barnes, Patrick M. Sexton, Steven M. Paul, Arthur Christopoulos, David M. Thal, Christian C. Felder, Celine Valant, Ron O. Dror
NATURE CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Alexander S. Powers, Vi Pham, Wessel A. C. Burger, Geoff Thompson, Yianni Laloudakis, Patrick M. Sexton, Steven M. Paul, Arthur Christopoulos, David M. Thal, Christian C. Felder, Celine Valant, Ron O. Dror
Summary: The selectivity of a drug for target receptors is crucial but challenging when the receptors are similar. Serendipitous discovery of ligands that stimulate target receptors more strongly than closely related receptors provides a solution. This study reveals the structural basis for the efficacy-driven selectivity of xanomeline, a clinical drug candidate, between closely related muscarinic acetylcholine receptors (mAChRs), using atomic-level simulations. The results suggest strategies for rational design of ligands achieving efficacy-driven selectivity for G-protein-coupled receptors.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Pharmacology & Pharmacy
Michael L. Garelja, Tyla I. Alexander, Amy Bennie, Mhairi Nimick, Jakeb Petersen, Christopher S. Walker, Debbie L. Hay
Summary: This study demonstrates that erenumab can antagonize both CGRP and AMY(1) receptors, providing insights into the clinical profile of erenumab.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Multidisciplinary Sciences
Wessel A. C. Burger, Vi Pham, Ziva Vuckovic, Alexander S. Powers, Jesse I. Mobbs, Yianni Laloudakis, Alisa Glukhova, Denise Wootten, Andrew B. Tobin, Patrick M. Sexton, Steven M. Paul, Christian C. Felder, Radostin Danev, Ron O. Dror, Arthur Christopoulos, Celine Valant, David M. Thal
Summary: The M4 muscarinic acetylcholine receptor is a significant drug target for the treatment of psychosis, cognition, and addiction. The clinical trial of xanomeline has shown promise in improving symptoms and the cryo-EM structure reveals the binding mechanism, providing insight into its complex pharmacology.
NATURE COMMUNICATIONS
(2023)
Meeting Abstract
Neurosciences
Wessel A. C. Burger, Vi Pham, Alexander Powers, Ziva Vuckovic, Jesse I. Mobbs, Alisa Glukhova, Denise Wootten, Andrew B. Tobin, Patrick M. Sexton, Steven M. Paul, Christian Felder, Radostin Danev, Arthur Christopoulos, Ron O. Dror, Celine Valant, David M. Thal
NEUROPSYCHOPHARMACOLOGY
(2022)
