A5086973728- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Mass Spectrometry Techniques and Applications
- Lipid Membrane Structure and Behavior
- Nitric Oxide and Endothelin Effects
- Neuroscience and Neuropharmacology Research
- Semiconductor materials and devices
- Protein Structure and Dynamics
- Fluorine in Organic Chemistry
- Drug Transport and Resistance Mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Cancer-related Molecular Pathways
- Neuroendocrine Tumor Research Advances
- Trace Elements in Health
- Circadian rhythm and melatonin
- Nanofabrication and Lithography Techniques
- Adsorption and biosorption for pollutant removal
- PARP inhibition in cancer therapy
- Proteins in Food Systems
- Nanomaterials for catalytic reactions
- Amino Acid Enzymes and Metabolism
- Biochemical and Structural Characterization
- DNA Repair Mechanisms
- Phosphodiesterase function and regulation
- Extraction and Separation Processes
Tsinghua University
2019-2025
Center for Life Sciences
2019-2025
Peking University
2023-2025
Shenzhen University Health Science Center
2025
Hubei University of Technology
2024
Beijing Advanced Sciences and Innovation Center
2023
Leipzig University
2023
University of Copenhagen
2023
Institute of Biophysics
2023
Stanford Medicine
2023
Drugs targeting the orthosteric, primary binding site of G protein-coupled receptors are most common therapeutics. Allosteric sites, elsewhere on receptors, less well-defined, and so exploited clinically. We report crystal structure prototypic β2-adrenergic receptor in complex with an orthosteric agonist compound-6FA, a positive allosteric modulator this receptor. It binds receptor's inner surface pocket created by intracellular loop 2 transmembrane segments 3 4, stabilizing α-helical...
Abstract The α 1A- adrenergic receptor (α 1A AR) belongs to the family of G protein-coupled receptors that respond adrenaline and noradrenaline. AR is involved in smooth muscle contraction cognitive function. Here, we present three cryo-electron microscopy structures human bound endogenous agonist noradrenaline, its selective oxymetazoline, antagonist tamsulosin, with resolutions range from 2.9 Å 3.5 Å. Our active inactive reveal activation mechanism distinct ligand binding modes for...
Abstract The human organic cation transporter 1 (hOCT1), also known as SLC22A1, is integral to hepatic uptake of structurally diversified endogenous and exogenous cations, influencing both metabolism drug pharmacokinetics. hOCT1 has been implicated in the therapeutic dynamics many drugs, making interactions with a key consideration novel development drug–drug interactions. Notably, metformin, frontline medication for type 2 diabetes, prominent substrate. Conversely, can be inhibited by...
Abstract G protein-coupled receptors (GPCRs) within the same subfamily often share high homology in their orthosteric pocket and therefore pose challenges to drug development. The amino acids that form binding for epinephrine norepinephrine β 1 2 adrenergic (β AR AR) are identical. Here, examine effect of conformational restriction on ligand kinetics, we synthesized a constrained epinephrine. Surprisingly, exhibits over 100-fold selectivity AR. We provide evidence may be due reduced...
GPCRs signal through both G protein pathways and β–arrestin pathways. Previous work suggests that β–arrestins bind to different modes, including core engagement tail engagement. Core competes with proteins terminates signaling, while can coexist proteins, mediating sustained intracellular activation of the receptor – a process dependent on high affinity between phosphorylated C-terminus receptor. In this study, we determined structure GPCR - β-arrestin-1 complex stabilized by an allosteric...
Approximately 1/3 of all clinical drugs exert their therapeutic effects by modulating the activity G protein-coupled receptors (GPCRs). Thus, there is a constant interest in finding novel ways to modulate GPCR activity. In this work, through newly established Survival Pressure Selection (SPS) method for high-throughput screening agonists, we discover that atazanavir functions as an agonist GPR119. Further studies suggest capable activating number Family A GPCRs, including β1 adrenergic...
Abstract Purinergic P2Y2 receptor (P2Y2R) represents a typically extracellular ATP and UTP sensor for mediating purinergic signaling. Despite its importance as pharmacological target, the molecular mechanisms underlying ligand recognition G-protein coupling have remained elusive due to lack of structural information. In this study, we determined cryo-electron microscopy (cryo-EM) structures apo P2Y2R in complex with G q , ATP-bound or o UTP-bound P2Y4R . These reveal similarities...
G protein-coupled receptors (GPCRs) are prominent drug targets that have attracted intensive efforts in screening. Binding-based screening methods for GPCR ligands often require conformationally stable, purified receptors. However, obtaining large quantities of GPCRs stable states, particularly with unoccupied extracellular ligand-binding pockets and especially their active conformations, remains challenging due to the inherent dynamic nature these To address this challenge, we propose a...
Abstract Prostaglandins and their receptors regulate various physiological processes. Carboprost, an analog of prostaglandin F 2α agonist for the F2-alpha receptor (FP receptor), is clinically used to treat postpartum hemorrhage (PPH). However, off-target activation closely related such as E subtype EP3 (EP3 receptor) by carboprost results in side effects limits clinical application. Meanwhile, FP selective latanoprost not suitable PPH due its poor solubility fast clearance. Here, we present...
Membrane proteins play essential roles in a number of biological processes, and their structures are important elucidating such processes at the molecular level also for rational drug design development. protein structure determination is notoriously challenging compared to that soluble proteins, due largely inherent instability non-lipid environments. Micelles formed by conventional detergents have been widely used membrane manipulation, but they suboptimal long-term stability making...
Abstract Development of subtype‐selective drugs for G protein‐coupled receptors poses a significant challenge due to high similarity between subtypes, as exemplified by the three β‐adrenergic (βARs). The β 3 AR agonists show promise treating overactive bladder or preterm birth, but their potential is hindered off‐target activation 1 and 2 AR. Interestingly, several β‐blockers, which are antagonists ARs ARs, have been reported exhibit agonist activity at However, molecular mechanism remains...
<title>Abstract</title> G protein-coupled receptors (GPCRs) activate heterotrimeric proteins by promoting guanine nucleotide exchange. Here, we investigate the process of functional association between and GPCRs describe events that ultimately lead to ejection GDP from its binding pocket in Gα subunit. In atomic detail, reveal temporal progression structural rearrangements GDP-bound Gs protein (GsGDP) upon coupling β2-adrenergic receptor (β2AR) using molecular dynamics simulations. The GsGDP...
Abstract G protein-coupled receptors (GPCRs) play pivotal roles in cellular signaling and represent prominent drug targets. Structural elucidation of GPCRs is crucial for discovery efforts. However, structural studies remain challenging, particularly inactive state structures, which often require extensive protein engineering. Here, we present a de novo design strategy termed “click fusion” generating fusion proteins to facilitate GPCR studies. Our method involves the rational structurally...
Abstract Prostaglandins and their receptors regulate various physiological processes, such as cardiovascular homeostasis, body temperature control female production. Carboprost, an analog of prostaglandin F2α agonist for the F2-alpha receptor (FP receptor), is clinically used to treat postpartum hemorrhage (PPH), which a leading cause maternal morbidity mortality. However, off-target activation closely related EP3 by carboprost results in side effects limits clinical application. Meanwhile,...