The impact of nanobodies on GPCR structural biology and their potential as therapeutic agents DOI Open Access
David Salom, Arum Wu, Chang C. Liu

et al.

Molecular Pharmacology, Journal Year: 2024, Volume and Issue: 106(4), P. 155 - 163

Published: Aug. 6, 2024

The family of human G protein-coupled receptors (GPCRs) is comprised about 800 different members, with 35% current pharmaceutical drugs targeting GPCRs. However, GPCR structural biology, necessary for structure-guided drug design, has lagged behind that other membrane proteins, and it was not until the year 2000 when first crystal structure a (rhodopsin) solved. Starting in 2007, determination additional structures facilitated by protein engineering, new crystallization techniques, complexation antibody fragments, strategies. More recently, use camelid heavy-chain-only fragments (nanobodies) as crystallographic chaperones revolutionized field aiding more than 340 to date. In most cases, solved complexes nanobodies (Nbs) have revealed binding mode cognate or non-natural ligands; few same Nb acted an orthosteric allosteric modulator signaling. this review we summarize multiple ingenious strategies been conceived implemented last decade capitalize on discovery study GPCRs from perspective. Significance Statement are major pharmacological targets, their at high resolution essential design insights functions. Single domain antibodies greatly GPCRs, forming directly indirectly through partners.

Language: Английский

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
Promiscuous G-protein activation by the calcium-sensing receptor DOI
Hao Zuo, Jinseo Park, Aurel Frangaj

et al.

Nature, Journal Year: 2024, Volume and Issue: 629(8011), P. 481 - 488

Published: April 17, 2024

Language: Английский

Citations

10
Symmetric activation and modulation of the human calcium-sensing receptor DOI Open Access
Jinseo Park, Hao Zuo, Aurel Frangaj

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(51)

Published: Dec. 16, 2021

Significance The human calcium-sensing receptor maintains a stable concentration of calcium in the blood. Naturally occurring mutations are linked to homeostatic disorders including hypercalcemia and hypocalcemia. Modulation function can provide therapeutic relief these conditions. structures absence presence various allosteric modulators reveal mechanism by which modifiers up- or down-regulate function. We have captured symmetric forms homodimeric both at rest upon stimulation concluded that activation involves conformational change its dimer interface. structural details different functional states may assist design new therapeutics for diseases related homeostasis.

Language: Английский

Citations

44
Allosteric modulation of GPCRs: From structural insights to in silico drug discovery DOI
Margherita Persechino,

Janik B. Hedderich,

Peter Kolb

et al.

Pharmacology & Therapeutics, Journal Year: 2022, Volume and Issue: 237, P. 108242 - 108242

Published: July 18, 2022

Language: Английский

Citations

36
Accelerating GPCR Drug Discovery With Conformation-Stabilizing VHHs DOI Creative Commons
Toon Laeremans, Zara A. Sands,

Pieter Claes

et al.

Frontiers in Molecular Biosciences, Journal Year: 2022, Volume and Issue: 9

Published: May 23, 2022

The human genome encodes 850 G protein-coupled receptors (GPCRs), half of which are considered potential drug targets. GPCRs transduce extracellular stimuli into a plethora vital physiological processes. Consequently, an attractive target class. This is underlined by the fact that approximately 40% marketed drugs modulate GPCRs. Intriguingly 60% non-olfactory have no or candidates in clinical development, highlighting continued as discovery small molecules targeting these conventional high throughput screening (HTS) campaigns challenging. Although definition success varies per company, rate HTS for low compared to other families ( Fujioka and Omori, 2012 ; Dragovich et al., 2022 ). Beyond this, GPCR structure determination can be difficult, often precludes application structure-based design approaches arising hits. structural studies entail resource-demanding purification native receptors, challenging they inherently unstable when extracted from lipid matrix. Moreover, flexible adopt distinct conformations, some need stabilized if structurally resolved. complexity therapeutically relevant conformations during early stages contributes attrition rates programs. Multiple strategies been explored attempt stabilize better understand their pharmacology. review will focus on use camelid-derived immunoglobulin single variable domains (VHHs) disease-relevant pharmacological states (termed ConfoBodies authors) GPCRs, well GPCR:signal transducer complexes, accelerate discovery. These VHHs powerful tools supporting vitro screening, deconvolution complex pharmacology, biology purposes. In order demonstrate impact translational research, examples presented role active state structure-informed rational identify de novo chemical space and, subsequently, how such matter elaborated more potent selective with intended

Language: Английский

Citations

34
Phenylalanine promotes alveolar macrophage pyroptosis via the activation of CaSR in ARDS DOI Creative Commons

Yiding Tang,

Yue Yu, Ranran Li

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: June 12, 2023

Acute respiratory distress syndrome (ARDS) is associated with high mortality rates in patients admitted to the intensive care unit (ICU) overwhelming inflammation considered be an internal cause. The authors’ previous study indicated a potential correlation between phenylalanine levels and lung injury. Phenylalanine induces by enhancing innate immune response release of pro-inflammatory cytokines. Alveolar macrophages (AMs) can respond stimuli via synthesis inflammatory mediators through pyroptosis, one form programmed cell death acting nucleotide-binging oligomerization domain-like receptors protein 3 (NLRP3) signaling pathway, resulting cleavage caspase-1 gasdermin D (GSDMD) interleukin (IL) -1β IL-18, aggravating injury ARDS. In this study, promoted pyroptosis AMs, which exacerbated ARDS lethality mice. Furthermore, initiated NLRP3 pathway activating calcium-sensing receptor (CaSR). These findings uncovered critical mechanism action context may new treatment target for

Language: Английский

Citations

18
The impact of cryo-EM on determining allosteric modulator-bound structures of G protein-coupled receptors DOI Open Access
Liudi Zhang, Jesse I. Mobbs, Lauren T. May

et al.

Current Opinion in Structural Biology, Journal Year: 2023, Volume and Issue: 79, P. 102560 - 102560

Published: Feb. 26, 2023

Language: Английский

Citations

13
Asymmetric activation of dimeric GABAB and metabotropic glutamate receptors DOI
Lei Liu, Li Lin,

Cangsong Shen

et al.

AJP Cell Physiology, Journal Year: 2023, Volume and Issue: 325(1), P. C79 - C89

Published: May 15, 2023

G protein-coupled receptors (GPCRs) represent the largest family of membrane proteins and are important drug targets. GPCRs allosteric machines that transduce an extracellular signal to cell by activating heterotrimeric proteins. Herein, we summarize recent advancements in molecular activation mechanism γ-aminobutyric acid type B (GABAB) metabotropic glutamate (mGlu) receptors, most class C modulate synaptic transmission brain. Both mandatory dimers, this quaternary structure being needed for their function The structures these different conformations complexes with have revealed asymmetric activation. This asymmetry is further highlighted discovery mGlu heterodimers, where eight subunits can form specific functional heterodimers. Finally, development modulators has new possibilities regulating targeting transmembrane dimer interface. never ceases astonish serve as models better understand diversity functioning GPCRs.NEW & NOTEWORTHY constitutive which required function. They (GPCRs). Allosteric be developed target interface asymmetry.

Language: Английский

Citations

11
Structural insights into the LGR4-RSPO2-ZNRF3 complexes regulating WNT/β-catenin signaling DOI Creative Commons
Lu Wang,

Fangzheng Hu,

Qianqian Cui

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 3, 2025

WNT/β-catenin signaling plays key roles in development and cancer1,2. ZNRF3/RNF43 modulates Frizzleds through ubiquitination, dampening signaling. Conversely, RSPO1-4 binding to LGR4-6 enhances signaling3–5. Here, we elucidate the overall landscape of architectures multiple LGR4, RSPO2, ZNRF3 assemblies, showcasing varying stoichiometries arrangements. These structures reveal that LGR4 RSPO2 capture distinct states ZNRF3. The intrinsic heterogeneity LGR4-RSPO2-ZNRF3 assembly is influenced by content. Particularly, complex with a 2:2:2 ratio, two protomers induce stabilize inactive state ZNRF3, characterized wide inward-open conformation transmembrane helices (TM helices). This specific promotes stable complex, facilitating LGR4-induced endocytosis In contrast, active dimeric bound single adopts coiled-coil TM dimerization RING domains. Our findings unveil how content mediates diverse leading conformational rearrangements regulate signaling, provide structural foundation for drug targeting Wnt-driven cancers. Wnt signalling pathway essential maintenance stem cells. authors modulate conformations heterogeneity, stabilising its enhance signalling. offer insights targeted therapies

Language: Английский

Citations

0
Preparation and Characterization of LGR5 LOOP Region-Specific Nanobodies DOI
Jia Li,

Huarui Qiao,

Yuting Ding

et al.

Protein Expression and Purification, Journal Year: 2025, Volume and Issue: unknown, P. 106680 - 106680

Published: Jan. 1, 2025

Language: Английский

Citations

0