A5104147676- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Monoclonal and Polyclonal Antibodies Research
- Biochemical Analysis and Sensing Techniques
- SARS-CoV-2 and COVID-19 Research
- Hypothalamic control of reproductive hormones
- Mass Spectrometry Techniques and Applications
- Diabetes Treatment and Management
- Ion channel regulation and function
- Biochemical and Molecular Research
- Complement system in diseases
- Erythrocyte Function and Pathophysiology
- Adenosine and Purinergic Signaling
- Thyroid Disorders and Treatments
- Bacillus and Francisella bacterial research
- Bone health and treatments
- Ship Hydrodynamics and Maneuverability
- Protein Kinase Regulation and GTPase Signaling
- Nitric Oxide and Endothelin Effects
- Neuroscience and Neuropharmacology Research
- Antimicrobial Peptides and Activities
- Pharmacological Receptor Mechanisms and Effects
- Metabolomics and Mass Spectrometry Studies
- Gout, Hyperuricemia, Uric Acid
- Maritime Transport Emissions and Efficiency
Shanghai Institute of Materia Medica
2021-2025
Chinese Academy of Sciences
2021-2025
Wuhan University of Technology
2018-2025
Nanjing University of Chinese Medicine
2023-2024
Ruijin Hospital
2024
Shanghai Jiao Tong University
2024
State Key Laboratory of Drug Research
2023
Macau University of Science and Technology
2022
Wuchang University of Technology
2018
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has become the dominant infective strain. We report structures of spike trimer on its own and in complex with angiotensin-converting enzyme (ACE2) or an anti-Omicron antibody. Most mutations are located surface protein change binding epitopes to many current antibodies. In ACE2-binding site, compensating strengthen receptor domain (RBD) ACE2. Both RBD apo form thermodynamically unstable. An unusual RBD-RBD...
Abstract The Omicron BA.2 variant has become a dominant infective strain worldwide. Receptor binding studies show that the spike trimer exhibits 11-fold and 2-fold higher potency in to human ACE2 than from wildtype (WT) BA.1 strains. structure of complexed with reveals all three receptor-binding domains (RBDs) are open conformation, ready for binding, thus providing basis increased infectivity strain. JMB2002, therapeutic antibody was shown efficiently inhibit BA.1, also shows potent...
Endogenous ions play important roles in the function and pharmacology of G protein-coupled receptors (GPCRs) with limited atomic evidence. In addition, compared protein subtypes Gs, Gi/o, Gq/11, insufficient structural evidence is accessible to understand coupling mechanism G12/13 by GPCRs. Orphan receptor GPR35, which predominantly expressed gastrointestinal tract closely related inflammatory bowel diseases (IBDs), stands out as a prototypical for investigating ionic modulation G13...
Abstract Endothelin system comprises three endogenous 21-amino-acid peptide ligands endothelin-1, -2, and -3 (ET-1/2/3), two G protein-coupled receptor (GPCR) subtypes—endothelin A (ET R) B R). Since ET-1, the first endothelin, was identified in 1988 as one of most potent endothelial cell-derived vasoconstrictor peptides with long-lasting actions, endothelin has attracted extensive attention due to its critical role vasoregulation close relevance cardiovascular-related diseases. Here we...
Abstract Melanin-concentrating hormone (MCH) is a cyclic neuropeptide that regulates food intake, energy balance, and other physiological functions by stimulating MCHR1 MCHR2 receptors, both of which are class A G protein-coupled receptors. predominately couples to inhibitory protein, i/o , can only couple q/11 . Here we present cryo-electron microscopy structures MCH-activated with i q at the global resolutions 3.01 Å 2.40 Å, respectively. These reveal MCH adopts consistent...
The "magic methyl effect" has facilitated the successful development of numerous pharmaceutical compounds. During HsClpP activators, we found that incorporating groups into bicyclic imipridone scaffolds significantly enhanced activator activity at enzymatic level. Further structure-activity relationship studies led to identification a highly promising compound, CLPP-2068, which exhibited an EC50 value 50.4 nM. Cryo-electron microscopy techniques and computational analyses demonstrated...
Abstract Biased allosteric modulators (BAMs) of G protein-coupled receptors (GPCRs) have been at the forefront drug discovery owing to their potential selectively stimulate therapeutically relevant signaling and avoid on-target side effects. Although structures GPCRs in complex with protein or GRK a BAM-bound state recently resolved, revealing that BAM can induce biased by directly modulating interactions between these two transducers, no GPCR–arrestin structure has yet determined, limiting...
Abstract Gout, a common and painful disease, stems from hyperuricemia, where elevated blood urate levels lead to crystal formation in joints kidneys. The human transporter 1 (hURAT1) plays critical role homeostasis by facilitating reabsorption the renal proximal tubule, making it key target for gout therapy. Pharmacological inhibition of hURAT1 with drugs such as dotinurad, benzbromarone, lesinurad, verinurad promotes excretion alleviates symptoms. Here, we present cryo-electron microscopy...
The prevailing trend in marine engineering towards large-scale ship design inherently reduces structural rigidity, amplifying fluid–structure interaction effects during extreme wave loading scenarios. Conventional ultimate strength assessment frameworks fail to account for such dynamic coupling mechanisms. To address this critical limitation, study proposes a novel hydroelasto-plastic framework and establishes time-dependent equations governing interactions through systematic integration of...
Neurokinin 3 receptor (NK3R) is a tachykinin essential for the hypothalamic-pituitary-gonadal axis. The endogenous peptide agonist neurokinin B (NKB) preferentially activates NK3R, while substance P (SP) binds to NK1R. In addition, SP analogue senktide more potently NK3R than NKB and SP. However, mechanisms of preferential binding activation remain elusive. Herein, we determined cryogenic electron microscopy (cryo-EM) structures NK3R-Gq complex bound NKB, senktide. three NK3R-Gq/peptide...
MRGPRX1, a Mas-related GPCR (MRGPR), is key receptor for itch perception and targeting MRGPRX1 may have potential to treat both chronic pain. Here we report cryo-EM structures of the MRGPRX1-Gi1 MRGPRX1-Gq trimers in complex with two peptide ligands, BAM8-22 CNF-Tx2. These reveal shallow orthosteric pocket its conformational plasticity sensing multiple different peptidic allergens. Distinct from MRGPRX2, contains unique feature at extracellular ends TM3 TM4 accommodate C-terminal "RF/RY"...
The Omicron variant of SARS-CoV-2 has rapidly become the dominant infective strain and focus efforts against ongoing COVID-19 pandemic. Here we report an extensive set structures spike trimer by its own or in complex with ACE2 anti-Omicron antibody. These reveal that most mutations are located on surface protein, which confer stronger binding nearly 10 folds but inactive epitopes resistant to many therapeutic antibodies. Importantly, both RBD closed conformation thermodynamically unstable,...
Niacin, an age-old lipid-lowering drug, acts through the hydroxycarboxylic acid receptor 2 (HCAR2), a G-protein-coupled (GPCR). Yet, its use is hindered by side effects like skin flushing. To address this, specific HCAR2 agonists, MK-6892 and GSK256073, with fewer adverse have been created. However, activation mechanism of niacin these new agonists not well understood. Here, we present three cryoelectron microscopy structures Gi-coupled bound to niacin, MK-6892, GSK256073. Our findings show...