Isoquinoline small molecule ligands are agonists and probe-dependent allosteric modulators of the glucagon subfamily of GPCRs DOI Creative Commons

Elita Yuliantie,

Phuc N. H. Trinh,

Caroline A. Hick

et al.

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 229, P. 116483 - 116483

Published: Aug. 13, 2024

Class B1 G protein-coupled receptors (GPCRs) are peptide hormone and well validated therapeutic targets, however development of non-peptide drugs targeting this class is challenging. Recently, a series isoquinoline-based derivates were reported in the patent literature as allosteric ligands for glucagon receptor subfamily, two compounds, LSN3451217 LSN3556672, used to facilitate structural studies with glucagon-like peptide-1 (GLP-1R) glucose dependent insulinotropic (GIPR) bound orthosteric agonists. Here we pharmacologically characterized stereoisomers across GPCR family. This revealed LSN3556672 isomers agonists (GCGR), GLP-1R, GIPR calcitonin (CTR), albeit degree agonism varied at each receptor. In contrast, more selective lower potency GCGR CTR no activity GIPR. All compounds also modulated peptide-mediated cyclic adenosine monophosphate (cAMP) signaling GIPR, lesser extent probe-dependent manner, modest positive modulation observed some peptides, negligible effects other peptides. contrast neutral or weak negative/positive was peptides assessed CTR. study expands our knowledge on may have implications future drug discovery efforts subfamily.

Language: Английский

Direct interrogation of context-dependent GPCR activity with a universal biosensor platform DOI Creative Commons
Remi Janicot,

Marcin Maziarz,

Jong‐Chan Park

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(6), P. 1527 - 1546.e25

Published: Feb. 26, 2024

Language: Английский

Citations

21
The Molecular Biology of Placental Transport of Calcium to the Human Foetus DOI Open Access
Valerie Walker

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(1), P. 383 - 383

Published: Jan. 4, 2025

From fertilisation to delivery, calcium must be transported into and within the foetoplacental unit for intracellular signalling. This requires very rapid, precisely located Ca2+ transfers. In addition, from around eighth week of gestation, increasing amounts routed directly maternal blood foetus bone mineralisation through a flow-through system, which does not impact concentration. These different processes are mediated by numerous membrane-sited channels, transporters, exchangers. Understanding mechanisms is essential direct interventions optimise foetal development postnatal health protect mother pre-eclampsia. Ethical issues limit availability human tissue study. Our insight placental handling advancing rapidly, enabled developing genetic, analytical, computer technology. Because their diverse sources, reports new findings scattered. review aims pull data together highlight areas uncertainty. Areas needing clarification include trafficking, membrane expression, recycling channels transporters in microvilli; metabolism vitamin D gestational diabetes pre-eclampsia; vascular effects increased endothelial Orai expression pregnancy-specific beta-1-glycoproteins PSG1 PSG9.

Language: Английский

Citations

2
Structure, function and drug discovery of GPCR signaling DOI Creative Commons
Lin Cheng, Fan Xia, Ziyan Li

et al.

Molecular Biomedicine, Journal Year: 2023, Volume and Issue: 4(1)

Published: Dec. 4, 2023

G protein-coupled receptors (GPCRs) are versatile and vital proteins involved in a wide array of physiological processes responses, such as sensory perception (e.g., vision, taste, smell), immune response, hormone regulation, neurotransmission. Their diverse essential roles the body make them significant focus for pharmaceutical research drug development. Currently, approximately 35% marketed drugs directly target GPCRs, underscoring their prominence therapeutic targets. Recent advances structural biology have substantially deepened our understanding GPCR activation mechanisms interactions with G-protein arrestin signaling pathways. This review offers an in-depth exploration both traditional recent methods structure analysis. It presents structure-based insights into ligand recognition receptor delves deeper canonical noncanonical pathways downstream GPCRs. Furthermore, it highlights advancements GPCR-related discovery Particular emphasis is placed on selective drugs, allosteric biased signaling, polyphamarcology, antibody drugs. Our goal to provide researchers thorough updated determination, pathway investigation, foundation aims propel forward-thinking approaches that drawing upon latest selectivity, activation, mechanisms.

Language: Английский

Citations

33
Molecular features of the ligand-free GLP-1R, GCGR and GIPR in complex with Gs proteins DOI Creative Commons

Zhaotong Cong,

Fenghui Zhao,

Yang Li

et al.

Cell Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: Feb. 13, 2024

Abstract Class B1 G protein-coupled receptors (GPCRs) are important regulators of many physiological functions such as glucose homeostasis, which is mainly mediated by three peptide hormones, i.e., glucagon-like peptide-1 (GLP-1), glucagon (GCG), and glucose-dependent insulinotropic polypeptide (GIP). They trigger a cascade signaling events leading to the formation an active agonist–receptor–G protein complex. However, intracellular signal transducers can also activate receptor independent extracellular stimuli, suggesting intrinsic role proteins in this process. Here, we report cryo-electron microscopy structures human GLP-1 (GLP-1R), GCG (GCGR), GIP (GIPR) complex with s without presence cognate ligands. These ligand-free complexes share similar architecture those bound endogenous peptides, which, alone directly opens binding cavity rewires orthosteric pocket stabilize state unseen before. While peptide-binding site partially occupied inward folded transmembrane helix 6 (TM6)–extracellular loop 3 (ECL3) juncture GIPR or segment GCGR ECL2, portion GLP-1R adopts conformation close state. Our findings offer valuable insights into distinct activation mechanisms these receptors. It possible that absence ligand, half domain mobilized help protein, turn rearranges form transitional conformation, facilitating entry N-terminus.

Language: Английский

Citations

11
Conformational transitions and activation of the adhesion receptor CD97 DOI Creative Commons
Chunyou Mao,

Ru-Jia Zhao,

Ying-Jun Dong

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(3), P. 570 - 583.e7

Published: Jan. 11, 2024

Language: Английский

Citations

10
De novodesign of miniprotein agonists and antagonists targeting G protein-coupled receptors DOI Creative Commons
Edin Muratspahić,

David Feldman,

David E. Kim

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 23, 2025

Abstract G protein-coupled receptors (GPCRs) play key roles in physiology and are central targets for drug discovery development, yet the design of protein agonists antagonists has been challenging as GPCRs integral membrane proteins conformationally dynamic. Here we describe computational de novo methods a high throughput “receptor diversion” microscopy based screen generating GPCR binding miniproteins with affinity, potency selectivity, use these to generate MRGPRX1 CXCR4, GLP1R, GIPR, GCGR CGRPR antagonists. Cryo-electron data reveals atomic-level agreement between designed experimentally determined structures CGRPR-bound MRGPRX1-bound agonists, confirming precise conformational control receptor function. Our screening approach opens new frontiers development.

Language: Английский

Citations

1
Proton perception and activation of a proton-sensing GPCR DOI

Li-Nan Chen,

Hui Zhou, Kun Xi

et al.

Molecular Cell, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

1
Heterogeneity of tethered agonist signaling in adhesion G protein-coupled receptors DOI
Andrew N. Dates, Daniel T.D. Jones, Jeffrey S. Smith

et al.

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(8), P. 1542 - 1553.e4

Published: April 11, 2024

Language: Английский

Citations

7
Unraveling the Interplay of Extracellular Domain Conformational Changes and Parathyroid Hormone Type 1 Receptor Activation in Class B1 G Protein-Coupled Receptors: Integrating Enhanced Sampling Molecular Dynamics Simulations and Markov State Models DOI
Mengrong Li, Xiaoxiao Zhang, Shu Li

et al.

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(4), P. 844 - 853

Published: Feb. 5, 2024

Parathyroid hormone (PTH) type 1 receptor (PTH1R), as a typical class B1 G protein-coupled (GPCR), is responsible for regulating bone turnover and maintaining calcium homeostasis, its dysregulation has been implicated in the development of several diseases. The extracellular domain (ECD) PTH1R crucial recognition binding ligands, may exhibit an autoinhibited state with closure ECD absence ligands. However, correlation between conformations activation remains unclear. Thus, this study combines enhanced sampling molecular dynamics (MD) simulations Markov models (MSMs) to reveal possible relevance PTH1R. First, 22 intermediate structures are generated from active conducted 10 independent 200 ns each. Then, MSM constructed based on cumulative 44 μs six identified microstates. Finally, potential interplay conformational changes well cryptic allosteric pockets states during revealed. Overall, our findings that specific provide essential insights GPCR biology developing novel modulators targeting sites.

Language: Английский

Citations

6
Highly biased agonism for GPCR ligands via nanobody tethering DOI Creative Commons
Shivani Sachdev,

Brendan A. Creemer,

Thomas J. Gardella

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 1, 2024

Abstract Ligand-induced activation of G protein-coupled receptors (GPCRs) can initiate signaling through multiple distinct pathways with differing biological and physiological outcomes. There is intense interest in understanding how variation GPCR ligand structure be used to promote pathway selective (“biased agonism”) the goal promoting desirable responses avoiding deleterious side effects. Here we present an approach which a conventional peptide for type 1 parathyroid hormone receptor (PTHR1) converted from agonist induces all relevant compound that highly single pathway. This achieved not core agonist, but rather by linking it nanobody tethering agent binds high affinity separate site on involved signal transduction. The resulting conjugate represents most biased PTHR1 reported date. holds promise facile generation ligands other GPCRs.

Language: Английский

Citations

6