A5070532479- Receptor Mechanisms and Signaling
- Neuropeptides and Animal Physiology
- Diabetes Treatment and Management
- Regulation of Appetite and Obesity
- Biochemical Analysis and Sensing Techniques
- Mass Spectrometry Techniques and Applications
- Computational Drug Discovery Methods
- Glycosylation and Glycoproteins Research
- Pancreatic function and diabetes
- Protein Kinase Regulation and GTPase Signaling
- Bone health and treatments
- Nanoparticle-Based Drug Delivery
- Ion channel regulation and function
- Chemical Synthesis and Analysis
- Characterization and Applications of Magnetic Nanoparticles
- Estrogen and related hormone effects
- melanin and skin pigmentation
- Monoclonal and Polyclonal Antibodies Research
- Macrophage Migration Inhibitory Factor
- Lanthanide and Transition Metal Complexes
- Growth Hormone and Insulin-like Growth Factors
- Neuroendocrine Tumor Research Advances
- Metabolism, Diabetes, and Cancer
- Mesoporous Materials and Catalysis
- Ion Transport and Channel Regulation
Shanghai Institute of Materia Medica
2016-2025
Chinese Academy of Sciences
2014-2025
National Center for Drug Screening
2016-2024
Shanghai Normal University
2011-2013
Class A G-protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology. Understanding receptor activation mechanism is critical for discovering novel therapeutics since about one-third all marketed drugs target members this family. GPCR an allosteric process that couples agonist binding to G-protein recruitment, with the hallmark outward movement transmembrane helix 6 (TM6). However, what leads TM6 and key residue level changes remain less well understood. Here, we...
The parathyroid hormone receptor-1 (PTH1R) is a class B G protein-coupled receptor central to calcium homeostasis and therapeutic target for osteoporosis hypoparathyroidism. Here we report the cryo-electron microscopy structure of human PTH1R bound long-acting PTH analog stimulatory protein. peptide adopts an extended helix with its amino terminus inserted deeply into transmembrane domain (TMD), which leads partial unwinding carboxyl 6 induces sharp kink at middle this allow couple In...
Abstract Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists at GIPR, GLP-1R or GCGR, developed maximize metabolic benefits with reduced side-effects, are in clinical trials treat type 2 diabetes obesity. To elucidate the molecular mechanisms which tirzepatide, a GIPR/GLP-1R dual agonist, peptide 20, GIPR/GLP-1R/GCGR triagonist, manifest their...
Choosing a partner that fits G protein–coupled receptors (GPCRs) are responsible for transducing diverse signals from outside to inside cells. This process requires specificity both in ligand binding GPCRs and coupling between their intracellular partners, proteins. Qiao et al. determined the structure of human glucagon receptor (GCGR), type B GPCR, bound one two heterotrimeric proteins, s or i1 . GCGR mainly through , structures provide basis this specificity. Conformational changes GCGR,...
Abstract Accurate identification of compound–protein interactions (CPIs) in silico may deepen our understanding the underlying mechanisms drug action and thus remarkably facilitate discovery development. Conventional similarity- or docking-based computational methods for predicting CPIs rarely exploit latent features from currently available large-scale unlabeled compound protein data often limit their usage to relatively small-scale datasets. In present study, we propose DeepCPI, a novel...
Abstract Cholecystokinin A receptor (CCK R) belongs to family G-protein-coupled receptors and regulates nutrient homeostasis upon stimulation by cholecystokinin (CCK). It is an attractive drug target for gastrointestinal metabolic diseases. One distinguishing feature of CCK R its ability interact with a sulfated ligand couple divergent G-protein subtypes, including G s , i q . However, the basis coupling promiscuity recognition remains unknown. Here, we present three cryo-electron microscopy...
Abstract Growth hormone-releasing hormone (GHRH) regulates the secretion of growth that virtually controls metabolism and every tissue through its binding to cognate receptor (GHRHR). Malfunction in GHRHR signaling is associated with abnormal growth, making an attractive therapeutic target against dwarfism (e.g., isolated deficiency, IGHD), gigantism, lipodystrophy certain cancers. Here, we report cryo-electron microscopy (cryo-EM) structure human bound endogenous ligand stimulatory G...
The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and efficacy enhancers orthosteric ligands. However, the molecular details ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) GLP-1; (iii) LY3502970 (a small molecule agonist), all in complex with heterotrimeric Gs....
The objective of this study was to evaluate the targeted T1-magnetic resonance imaging (MRI), quantitative biodistribution and toxicity aptamer (AS411) conjugated Mn3O4@SiO2 core–shell nanoprobes (NPs) in human cervical carcinoma tumor-bearing mice. NPs were firstly prepared by encapsulating a hydrophobic Mn3O4 core within an amino functionalized silica shell. fluorophore rhodamine (RB) doped into shell amphiphilic polymer poly(ethylene glycol) (PEG) modified on surface improve its...
Abstract 5-hydroxytryptamine (5-HT, also known as serotonin) regulates many physiological processes through the 5-HT receptor family. Here we report crystal structure of 1B subtype (5-HT R) bound to psychotropic serotonin inverse agonist methiothepin (MT). Crystallization was facilitated by replacing ICL3 with a novel optimized variant BRIL (OB1) that enhances formation intermolecular polar interactions, making OB1 potential useful tool for structural studies membrane proteins. Unlike...
G protein-coupled receptors (GPCRs) from the secretin-like (class B) family are key players in hormonal homeostasis and important drug targets for treatment of metabolic disorders neuronal diseases. They consist a large N-terminal extracellular domain (ECD) transmembrane (TMD) with GPCR signature seven helices. Class B GPCRs activated by peptide hormones their C termini bound to receptor ECD N TMD. It is thought that functions as an affinity trap bind localize hormone receptor. This turn...
Abstract Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, thus are considered targets for treating tumors. Despite great progress made therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity conspicuous side-effects. Here, we report five structures SSTR2 SSTR4 different states, including two...
The glucagon-like peptide-1 receptor (GLP-1R) belongs to the secretin-like (class B) family of G protein-coupled receptors. Members class B are distinguished by their large extracellular domain, which works cooperatively with canonical seven-transmembrane (7TM) helical domain signal in response binding various peptide hormones. We have combined structure-based site-specific mutational studies molecular dynamics simulations a full-length model GLP-1R bound multiple ligand variants. Despite...
Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone that exerts crucial metabolic functions by binding and activating its cognate receptor, GIPR. As an important therapeutic target, GIPR has been subjected to intensive structural studies without success. Here, we report the cryo-EM structure of human in complex with GIP G