keyword
https://read.qxmd.com/read/38395122/gpcrs-in-the-round-sma-like-copolymers-and-smalps-as-a-platform-for-investigating-gpcrs
#21
JOURNAL ARTICLE
Hoor Ayub, Rebecca J Murray, Gestél C Kuyler, Farhaan Napier-Khwaja, Joseph Gunner, Tim R Dafforn, Bert Klumperman, David R Poyner, Mark Wheatley
G-protein-coupled receptors (GPCRs) are the largest family of membrane proteins, regulate a plethora of physiological responses and are the therapeutic target for 30-40% of clinically-prescribed drugs. They are integral membrane proteins deeply embedded in the plasma membrane where they activate intracellular signalling via coupling to G-proteins and β-arrestin. GPCRs are in intimate association with the bilayer lipids and that lipid environment regulates the signalling functions of GPCRs. This complex lipid 'landscape' is both heterogeneous and dynamic...
February 21, 2024: Archives of Biochemistry and Biophysics
https://read.qxmd.com/read/38391238/probing-activation-and-conformational-dynamics-of-the-vesicle-reconstituted-%C3%AE-2-adrenergic-receptor-at-the-single-molecule-level
#22
JOURNAL ARTICLE
Marijonas Tutkus, Christian V Lundgaard, Salome Veshaguri, Asger Tønnesen, Nikos Hatzakis, Søren G F Rasmussen, Dimitrios Stamou
G-protein-coupled receptors (GPCRs) are structurally flexible membrane proteins that mediate a host of physiological responses to extracellular ligands like hormones and neurotransmitters. Fine features of their dynamic structural behavior are hypothesized to encode the functional plasticity seen in GPCR activity, where ligands with different efficacies can direct the same receptor toward different signaling phenotypes. Although the number of GPCR crystal structures is increasing, the receptors are characterized by complex and poorly understood conformational landscapes...
February 23, 2024: Journal of Physical Chemistry. B
https://read.qxmd.com/read/38387741/orphan-gpr52-as-an-emerging-neurotherapeutic-target
#23
REVIEW
Saghir Ali, Pingyuan Wang, Ryan E Murphy, John A Allen, Jia Zhou
GPR52 is a highly conserved, brain-enriched, Gs/olf -coupled orphan G protein-coupled receptor (GPCR) that controls various cyclic AMP (cAMP)-dependent physiological and pathological processes. Stimulation of GPR52 activity might be beneficial for the treatment of schizophrenia, psychiatric disorders and other human neurological diseases, whereas inhibition of its activity might provide a potential therapeutic approach for Huntington's disease. Excitingly, HTL0048149 (HTL'149), an orally available GPR52 agonist, has been advanced into phase I human clinical trials for the treatment of schizophrenia...
February 20, 2024: Drug Discovery Today
https://read.qxmd.com/read/38385828/fragment-based-design-synthesis-and-characterization-of-aminoisoindole-derived-furin-inhibitors
#24
JOURNAL ARTICLE
Roman W Lange, Konstantin Bloch, Miriam Ruth Heindl, Jan Wollenhaupt, Manfred S Weiss, Hans Brandstetter, Gerhard Klebe, Franco H Falcone, Eva Böttcher-Friebertshäuser, Sven O Dahms, Torsten Steinmetzer
A 1H-isoindol-3-amine was identified as suitable P1 group for the proprotein convertase furin using a crystallographic screening with a set of 20 fragments known to occupy the S1 pocket of trypsin-like serine proteases. Its binding mode is very similar to that observed for the P1 group of benzamidine-derived peptidic furin inhibitors suggesting an aminomethyl substitution of this fragment to obtain a couplable P1 residue for the synthesis of substrate-analogue furin inhibitors. The obtained inhibitors possess a slightly improved picomolar inhibitory potency compared to their benzamidine-derived analogues...
February 22, 2024: ChemMedChem
https://read.qxmd.com/read/38384797/direct-modulation-of-trpc-ion-channels-by-g%C3%AE-proteins
#25
REVIEW
Hana Kang, Jinhyeong Kim, Christine Haewon Park, Byeongseok Jeong, Insuk So
GPCR-Gi protein pathways are involved in the regulation of vagus muscarinic pathway under physiological conditions and are closely associated with the regulation of internal visceral organs. The muscarinic receptor-operated cationic channel is important in GPCR-Gi protein signal transduction as it decreases heart rate and increases GI rhythm frequency. In the SA node of the heart, acetylcholine binds to the M2 receptor and the released Gβγ activates GIRK (I(K,ACh)) channel, inducing a negative chronotropic action...
2024: Frontiers in Physiology
https://read.qxmd.com/read/38382646/exploring-diverse-signaling-mechanisms-of-g-protein-coupled-receptors-through-structural-biology
#26
JOURNAL ARTICLE
Ryoji Suno
Recent advancements in structural biology have facilitated the elucidation of complexes involving G protein-coupled receptors (GPCRs) and their associated signal transducers, including G proteins and arrestins. A comprehensive analysis of these structures provides profound insights into the dynamics of signaling mechanisms. These structural revelations can potentially guide the development of drugs to minimize side effects through targeted and selective signaling. Understanding the binding modes of different signal-selective ligands is imperative for future drug research and development...
February 21, 2024: Journal of Biochemistry
https://read.qxmd.com/read/38380648/a-bright-future-a-perspective-on-class-c-gpcr-based-genetically-encoded-biosensors
#27
REVIEW
Margulan Otanuly, Martin Kubitschke, Olivia Andrea Masseck
One of the major challenges in molecular neuroscience today is to accurately monitor neurotransmitters, neuromodulators, peptides, and various other biomolecules in the brain with high temporal and spatial resolution. Only a comprehensive understanding of neuromodulator dynamics, their release probability, and spatial distribution will unravel their ultimate role in cognition and behavior. This Perspective offers an overview of potential design strategies for class C GPCR-based biosensors. It briefly highlights current applications of GPCR-based biosensors, with a primary focus on class C GPCRs and their unique structural characteristics compared with other GPCR subfamilies...
February 21, 2024: ACS Chemical Neuroscience
https://read.qxmd.com/read/38376112/lipid-dependent-activation-of-the-orphan-g-protein-coupled-receptor-gpr3
#28
JOURNAL ARTICLE
Isabella C Russell, Xin Zhang, Fabian Bumbak, Samantha M McNeill, Tracy M Josephs, Michael G Leeming, George Christopoulos, Hariprasad Venugopal, Maria M Flocco, Patrick M Sexton, Denise Wootten, Matthew J Belousoff
The class A orphan G protein-coupled receptor (GPCR), GPR3, has been implicated in a variety of conditions, including Alzheimer's and premature ovarian failure. GPR3 constitutively couples with Gαs, resulting in the production of cAMP in cells. While tool compounds and several putative endogenous ligands have emerged for the receptor, its endogenous ligand, if it exists, remains a mystery. As novel potential drug targets, the structures of orphan GPCRs have been of increasing interest, revealing distinct modes of activation, including autoactivation, presence of constitutively activating mutations, or via cryptic ligands...
February 20, 2024: Biochemistry
https://read.qxmd.com/read/38373379/the-full-length-tsh-receptor-is-stabilized-by-tsh-ligand
#29
JOURNAL ARTICLE
Mihaly Mezei, Rauf Latif, Terry F Davies
The receptor for thyroid stimulating hormone (TSHR), a GPCR, is the primary antigen in autoimmune hyperthyroidism (Graves' disease) caused by stimulating TSHR antibodies. While we have previously published a full length model of the TSHR, including its leucine rich domain (LRD), linker region (LR) and transmembrane domain (TMD), to date, only a partial LRD (aa 21-261) stabilized with TSHR autoantibodies has been crystallized. Recently, however, cryo-EM structures of the full-length TSHR have been published but they include only an incomplete LR...
February 11, 2024: Journal of Molecular Graphics & Modelling
https://read.qxmd.com/read/38372466/discovery-of-a-photoaffinity-probe-that-captures-the-active-conformation-of-the-cannabinoid-cb2-receptor
#30
JOURNAL ARTICLE
Laura V de Paus, Yu An, Antonius P A Janssen, Richard J B H N Van den Berg, Laura H Heitman, Mario Van der Stelt
The cannabinoid receptor type 2 (CB2R) is a G protein-coupled receptor with therapeutic potential for the treatment of inflammatory disorders. Fluorescent probes are desirable to study its receptor localization, expression and occupancy. Previously, we have reported a photoaffinity probe LEI-121 that stabilized the inactive conformation of the CB2R. Here, we report the structure-based design of a novel bifunctional probe that captures the active conformation of the CB2R upon irradiation with light. An alkyne handle was incorporated to visualize the receptor using click-chemistry with fluorophore-azides...
February 19, 2024: Chembiochem: a European Journal of Chemical Biology
https://read.qxmd.com/read/38364891/heterotrimeric-g-protein-signaling-without-gpcrs-the-g%C3%AE-binding-and-activating-gba-motif
#31
REVIEW
Mikel Garcia-Marcos
Heterotrimeric G proteins (Gαβγ) are molecular switches that relay signals from 7-transmembrane receptors located at the cell surface to the cytoplasm. The function of these receptors is so intimately linked to heterotrimeric G proteins that they are named G protein-coupled receptors (GPCRs), showcasing the interdependent nature of this archetypical receptor-transducer axis of transmembrane signaling in eukaryotes. It is generally assumed that activation of heterotrimeric G protein signaling occurs exclusively by the action of GPCRs, but this idea has been challenged by the discovery of alternative mechanisms by which G proteins can propagate signals in the cell...
February 14, 2024: Journal of Biological Chemistry
https://read.qxmd.com/read/38362334/introduction-of-session-8-structural-mechanism-of-animal-rhodopsins-and-gpcr
#32
JOURNAL ARTICLE
Takeshi Murata
No abstract text is available yet for this article.
March 21, 2023: Biophysics and Physicobiology
https://read.qxmd.com/read/38352381/structure-guided-engineering-of-a-fast-genetically-encoded-sensor-for-real-time-h-2-o-2-monitoring
#33
Justin Daho Lee, Woojin Won, Kandace Kimball, Yihan Wang, Fred Yeboah, Kira M Evitts, Carlie Neiswanger, Selena Schattauer, Michael Rappleye, Samantha B Bremner, Changho Chun, Netta Smith, David L Mack, Jessica E Young, C Justin Lee, Charles Chavkin, Andre Berndt
Hydrogen Peroxide (H 2 O 2 ) is a central oxidant in redox biology due to its pleiotropic role in physiology and pathology. However, real-time monitoring of H 2 O 2 in living cells and tissues remains a challenge. We address this gap with the development of an optogenetic hydRogen perOxide Sensor (oROS), leveraging the bacterial peroxide binding domain OxyR. Previously engineered OxyR-based fluorescent peroxide sensors lack the necessary sensitivity or response speed for effective real-time monitoring. By structurally redesigning the fusion of Escherichia coli (E...
February 4, 2024: bioRxiv
https://read.qxmd.com/read/38352316/visualizing-the-impact-of-disease-associated-mutations-on-g-protein-nucleotide-interactions
#34
Kara Anazia, Lucien Koenekoop, Guillaume Ferré, Enzo Petracco, Hugo Gutiérrez-de-Teran, Matthew T Eddy
Activation of G proteins stimulates ubiquitous intracellular signaling cascades essential for life processes. Under normal physiological conditions, nucleotide exchange is initiated upon the formation of complexes between a G protein and G protein-coupled receptor (GPCR), which facilitates exchange of bound GDP for GTP, subsequently dissociating the trimeric G protein into its Gα and Gβγ subunits. However, single point mutations in Gα circumvent nucleotide exchange regulated by GPCR-G protein interactions, leading to either loss-of-function or constitutive gain-of-function...
February 1, 2024: bioRxiv
https://read.qxmd.com/read/38346795/pharmacological-characterization-and-radiolabeling-of-vuf15485-a-high-affinity-small-molecule-agonist-for-the-atypical-chemokine-receptor-ackr3
#35
JOURNAL ARTICLE
Aurelien Zarca, Ilze Adlere, Cristina P Viciano, Marta Arimont-Segura, Max Meyrath, Icaro A Simon, Jan Paul Bebelman, Dennis Laan, Hans G J Custers, Elwin Janssen, Kobus L K Versteegh, Maurice Buzink, Desislava Nesheva, Reggie Bosma, Iwan J P de Esch, Henry Vischer, Maikel Wijtmans, Martyna Szpakowska, Andy Chevigné, Carsten Hoffmann, Chris de Graaf, Barbara A Zarzycka, Albert D Windhorst, Martine J Smit, Rob Leurs
Atypical chemokine receptor 3 (ACKR3 is considered to be an interesting drug target. In this study we report on the synthesis, pharmacological characterization and radiolabeling of VUF15485, a new small-molecule agonist. VUF15485 binds with nanomolar affinity (pIC50 = 8.3) to human ACKR3, as measured in [125I]CXCL12 competition experiments. Moreover, in a BRET-based β-arrestin2 recruitment assay VUF15485 acts as an ACKR3 agonist with high potency (pEC50 = 7.6) and shows a similar extent of receptor activation compared to CXCL12 when using a newly developed, FRET-based ACKR3 conformational sensor...
February 12, 2024: Molecular Pharmacology
https://read.qxmd.com/read/38346183/fine-tuning-activation-specificity-of-g-protein-coupled-receptors-via-automated-path-searching
#36
JOURNAL ARTICLE
Rujuan Ti, Bin Pang, Leiye Yu, Bing Gan, Wenzhuo Ma, Arieh Warshel, Ruobing Ren, Lizhe Zhu
Physics-based simulation methods can grant atomistic insights into the molecular origin of the function of biomolecules. However, the potential of such approaches has been hindered by their low efficiency, including in the design of selective agonists where simulations of myriad protein-ligand combinations are necessary. Here, we describe an automated input-free path searching protocol that offers (within 14 d using Graphics Processing Unit servers) a minimum free energy path (MFEP) defined in high-dimension configurational space for activating sphingosine-1-phosphate receptors (S1PRs) by arbitrary ligands...
February 20, 2024: Proceedings of the National Academy of Sciences of the United States of America
https://read.qxmd.com/read/38340054/gpcr-bert-interpreting-sequential-design-of-g-protein-coupled-receptors-using-protein-language-models
#37
JOURNAL ARTICLE
Seongwon Kim, Parisa Mollaei, Akshay Antony, Rishikesh Magar, Amir Barati Farimani
With the rise of transformers and large language models (LLMs) in chemistry and biology, new avenues for the design and understanding of therapeutics have been opened up to the scientific community. Protein sequences can be modeled as language and can take advantage of recent advances in LLMs, specifically with the abundance of our access to the protein sequence data sets. In this letter, we developed the GPCR-BERT model for understanding the sequential design of G protein-coupled receptors (GPCRs). GPCRs are the target of over one-third of Food and Drug Administration-approved pharmaceuticals...
February 10, 2024: Journal of Chemical Information and Modeling
https://read.qxmd.com/read/38332368/constitutive-activation-mechanism-of-a-class-c-gpcr
#38
JOURNAL ARTICLE
Jinwoo Shin, Junhyeon Park, Jieun Jeong, Jordy Homing Lam, Xingyu Qiu, Di Wu, Kuglae Kim, Joo-Youn Lee, Carol V Robinson, Jaekyung Hyun, Vsevolod Katritch, Kwang Pyo Kim, Yunje Cho
Class C G-protein-coupled receptors (GPCRs) are activated through binding of agonists to the large extracellular domain (ECD) followed by rearrangement of the transmembrane domains (TMDs). GPR156, a class C orphan GPCR, is unique because it lacks an ECD and exhibits constitutive activity. Impaired GPR156-Gi signaling contributes to loss of hearing. Here we present the cryo-electron microscopy structures of human GPR156 in the Go -free and Go -coupled states. We found that an endogenous phospholipid molecule is located within each TMD of the GPR156 dimer...
February 8, 2024: Nature Structural & Molecular Biology
https://read.qxmd.com/read/38328199/structure-of-the-extracellular-region-of-the-adhesion-gpcr-celsr1-reveals-a-compact-module-which-regulates-g-protein-coupling
#39
Sumit J Bandekar, Krassimira Garbett, Szymon P Kordon, Ethan Dintzner, Tanner Shearer, Richard C Sando, Demet Araç
Cadherin EGF Laminin G seven-pass G-type receptors (CELSRs or ADGRCs) are conserved adhesion G protein-coupled receptors which are essential for animal development. CELSRs have extracellular regions (ECRs) containing 23 adhesion domains which couple adhesion to intracellular signaling. However, molecular-level insight into CELSR function is sparsely available. We report the 4.3 Å cryo-EM reconstruction of the mCELSR1 ECR with 13 domains resolved in the structure. These domains form a compact module mediated by interdomain interactions with contact between the N- and C-terminal domains...
January 27, 2024: bioRxiv
https://read.qxmd.com/read/38326651/gpr161-structure-uncovers-the-redundant-role-of-sterol-regulated-ciliary-camp-signaling-in-the-hedgehog-pathway
#40
JOURNAL ARTICLE
Nicholas Hoppe, Simone Harrison, Sun-Hee Hwang, Ziwei Chen, Masha Karelina, Ishan Deshpande, Carl-Mikael Suomivuori, Vivek R Palicharla, Samuel P Berry, Philipp Tschaikner, Dominik Regele, Douglas F Covey, Eduard Stefan, Debora S Marks, Jeremy F Reiter, Ron O Dror, Alex S Evers, Saikat Mukhopadhyay, Aashish Manglik
The orphan G protein-coupled receptor (GPCR) GPR161 plays a central role in development by suppressing Hedgehog signaling. The fundamental basis of how GPR161 is activated remains unclear. Here, we determined a cryogenic-electron microscopy structure of active human GPR161 bound to heterotrimeric Gs . This structure revealed an extracellular loop 2 that occupies the canonical GPCR orthosteric ligand pocket. Furthermore, a sterol that binds adjacent to transmembrane helices 6 and 7 stabilizes a GPR161 conformation required for Gs coupling...
February 7, 2024: Nature Structural & Molecular Biology
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