Structural Basis of Frizzled 7 Activation and Allosteric Regulation DOI Creative Commons
Gunnar Schulte, Julien Bous, Julia Kinsolving

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: May 14, 2024

Abstract Frizzleds (ten paralogs: FZD1 − 10) belong to the class F of G protein-coupled receptors (GPCRs), which remains poorly understood despite its crucial role in multiple key biological functions including embryonic development, stem cell regulation, and homeostasis adult. FZD7, one most studied members family, is more specifically involved migration mesendoderm cells during development renewal intestinal adults. Moreover, FZD7 has been highlighted for involvement tumor predominantly gastrointestinal tract. This study reports structure inactive without any stabilizing mutations, determined by cryo-electron microscopy (cryo-EM) at 1.9Å resolution. We characterized a fluctuating water pocket core receptor important dynamics. Molecular dynamics simulations were then used investigate temporal distribution those molecules their importance potential conformational changes FZD7. we identified lipids interacting with conserved cholesterol-binding site, displays association transducer protein, Dishevelled (DVL), initiation downstream signaling signalosome formation. Teaser Structural analysis reveals functional cholesterol critical signaling.

Language: Английский

GPCR drug discovery: new agents, targets and indications DOI
José A. Lorente, Aleksandr V. Sokolov, Gavin Ferguson

et al.

Nature Reviews Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Language: Английский

Citations

1
Genome-wide pan-GPCR cell libraries accelerate drug discovery DOI Creative Commons
Hanting Yang, Yongfu Wang, Wei Liu

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(10), P. 4296 - 4311

Published: June 26, 2024

G protein-coupled receptors (GPCRs) are pivotal in mediating diverse physiological and pathological processes, rendering them promising targets for drug discovery. GPCRs account about 40% of FDA-approved drugs, representing the most successful targets. However, only approximately 15% 800 human targeted by market leaving numerous opportunities discovery among remaining receptors. Cell expression systems play crucial roles GPCR field, including novel target identification, structural functional characterization, potential ligand screening, signal pathway elucidation, safety evaluation. Here, we discuss principles, applications, limitations widely used cell GPCR-targeted discovery, function investigation, pharmacological property studies. We also propose three strategies constructing genome-wide pan-GPCR libraries, which will provide a powerful platform facilitate study mechanisms evaluation, ultimately accelerating process

Language: Английский

Citations

7
Cryo-EM as a tool for illuminating activation mechanisms of human class A orphan GPCRs DOI Creative Commons
Isabella C. Russell,

Dongju Lee,

Denise Wootten

et al.

Pharmacological Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 100056 - 100056

Published: April 1, 2025

Language: Английский

Citations

0
Structural basis of frizzled 7 activation and allosteric regulation DOI Creative Commons
Julien Bous, Julia Kinsolving, Lukas Grätz

et al.

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

Published: Aug. 28, 2024

Frizzleds (ten paralogs: FZD

Language: Английский

Citations

2
The path to the G protein‐coupled receptor structural landscape: Major milestones and future directions DOI Creative Commons
Małgorzata M. Kogut,

Zeenat Zara,

Alessandro Nicoli

et al.

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 29, 2024

G protein-coupled receptors (GPCRs) play a crucial role in cell function by transducing signals from the extracellular environment to inside of cell. They mediate effects various stimuli, including hormones, neurotransmitters, ions, photons, food tastants and odorants, are renowned drug targets. Advancements structural biology techniques, X-ray crystallography cryo-electron microscopy (cryo-EM), have driven elucidation an increasing number GPCR structures. These structures reveal novel features that shed light on receptor activation, dimerization oligomerization, dichotomy between orthosteric allosteric modulation, intricate interactions underlying signal transduction, providing insights into diverse ligand-binding modes signalling pathways. However, substantial portion repertoire their activation states remain structurally unexplored. Future efforts should prioritize capturing full diversity GPCRs across multiple dimensions. To do so, integration with biophysical computational techniques will be essential. We describe this review progress nuclear magnetic resonance (NMR) examine plasticity conformational dynamics, atomic force (AFM) explore spatial-temporal dynamics kinetic aspects GPCRs, recent breakthroughs artificial intelligence for protein structure prediction characterize entire GPCRome. In summary, journey through provided illustrates how far we come decoding these essential proteins architecture function. Looking ahead, integrating cutting-edge biophysics tools offers path navigating landscape, ultimately advancing GPCR-based applications.

Language: Английский

Citations

1
Structural Basis of Frizzled 7 Activation and Allosteric Regulation DOI Creative Commons
Gunnar Schulte, Julien Bous, Julia Kinsolving

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: May 14, 2024

Abstract Frizzleds (ten paralogs: FZD1 − 10) belong to the class F of G protein-coupled receptors (GPCRs), which remains poorly understood despite its crucial role in multiple key biological functions including embryonic development, stem cell regulation, and homeostasis adult. FZD7, one most studied members family, is more specifically involved migration mesendoderm cells during development renewal intestinal adults. Moreover, FZD7 has been highlighted for involvement tumor predominantly gastrointestinal tract. This study reports structure inactive without any stabilizing mutations, determined by cryo-electron microscopy (cryo-EM) at 1.9Å resolution. We characterized a fluctuating water pocket core receptor important dynamics. Molecular dynamics simulations were then used investigate temporal distribution those molecules their importance potential conformational changes FZD7. we identified lipids interacting with conserved cholesterol-binding site, displays association transducer protein, Dishevelled (DVL), initiation downstream signaling signalosome formation. Teaser Structural analysis reveals functional cholesterol critical signaling.

Language: Английский

Citations

0