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Arthritis Research & Therapy Jul 2023Osteoarthritis (OA) is a prevalent degenerative disease accompanied by the activation of innate and adaptive immune systems-associated inflammatory responses. Due to the... (Review)
Review
Osteoarthritis (OA) is a prevalent degenerative disease accompanied by the activation of innate and adaptive immune systems-associated inflammatory responses. Due to the local inflammation, the expression of various cytokines was altered in affected joints, including CC motif chemokine ligands (CCLs) and their receptors (CCRs). As essential members of chemokines, CCLs and CCRs played an important role in the pathogenesis and treatment of OA. The bindings between CCLs and CCRs on the chondrocyte membrane promoted chondrocyte apoptosis and the release of multiple matrix-degrading enzymes, which resulted in cartilage degradation. In addition, CCLs and CCRs had chemoattractant functions to attract various immune cells to osteoarthritic joints, further leading to the aggravation of local inflammation. Furthermore, in the nerve endings of joints, CCLs and CCRs, along with several cellular factors, contributed to pain hypersensitivity by releasing neurotransmitters in the spinal cord. Given this family's diverse and complex functions, targeting the functional network of CCLs and CCRs is a promising strategy for the prognosis and treatment of OA in the future.
Topics: Humans; Chemokines, CC; Cartilage, Articular; Osteoarthritis; Chemokines; Inflammation; Chondrocytes
PubMed: 37400871
DOI: 10.1186/s13075-023-03096-6 -
ELife Jul 2023Receptors signal by switching between resting (C) and active (O) shapes ('gating') under the influence of agonists. The receptor's maximum response depends on the...
Receptors signal by switching between resting (C) and active (O) shapes ('gating') under the influence of agonists. The receptor's maximum response depends on the difference in agonist binding energy, O minus C. In nicotinic receptors, efficiency (η) represents the fraction of agonist binding energy applied to a local rearrangement (an induced fit) that initiates gating. In this receptor, free energy changes in gating and binding can be interchanged by the conversion factor η. Efficiencies estimated from concentration-response curves (23 agonists, 53 mutations) sort into five discrete classes (%): 0.56 (17), 0.51(32), 0.45(13), 0.41(26), and 0.31(12), implying that there are 5 C versus O binding site structural pairs. Within each class efficacy and affinity are corelated linearly, but multiple classes hide this relationship. η unites agonist binding with receptor gating and calibrates one link in a chain of coupled domain rearrangements that comprises the allosteric transition of the protein.
Topics: Receptors, Nicotinic; Binding Sites; Mutation
PubMed: 37399234
DOI: 10.7554/eLife.86496 -
Cell Reports Jul 2023The adhesion G-protein-coupled receptor GPR133 (ADGRD1) supports growth of the brain malignancy glioblastoma. How the extracellular interactome of GPR133 in glioblastoma...
The adhesion G-protein-coupled receptor GPR133 (ADGRD1) supports growth of the brain malignancy glioblastoma. How the extracellular interactome of GPR133 in glioblastoma modulates signaling remains unknown. Here, we use affinity proteomics to identify the transmembrane protein PTK7 as an extracellular binding partner of GPR133 in glioblastoma. PTK7 binds the autoproteolytically generated N-terminal fragment of GPR133 and its expression in trans increases GPR133 signaling. This effect requires the intramolecular cleavage of GPR133 and PTK7's anchoring in the plasma membrane. PTK7's allosteric action on GPR133 signaling is additive with but topographically distinct from orthosteric activation by soluble peptide mimicking the endogenous tethered Stachel agonist. GPR133 and PTK7 are expressed in adjacent cells in glioblastoma, where their knockdown phenocopies each other. We propose that this ligand-receptor interaction is relevant to the pathogenesis of glioblastoma and possibly other physiological processes in healthy tissues.
Topics: Humans; Glioblastoma; Signal Transduction; Receptors, G-Protein-Coupled; Cell Membrane; Allosteric Regulation; Ligands; Allosteric Site; Cell Adhesion Molecules; Receptor Protein-Tyrosine Kinases
PubMed: 37354459
DOI: 10.1016/j.celrep.2023.112679 -
Computational and Structural... Dec 2024Coronaviruses (CoVs) pose a major risk to global public health due to their ability to infect diverse animal species and potential for emergence in humans. The CoV spike... (Review)
Review
Coronaviruses (CoVs) pose a major risk to global public health due to their ability to infect diverse animal species and potential for emergence in humans. The CoV spike protein mediates viral entry into the cell and plays a crucial role in determining the binding affinity to host cell receptors. With particular emphasis on α- and β-coronaviruses that infect humans and domestic animals, current research on CoV receptor use suggests that the exploitation of the angiotensin-converting enzyme 2 (ACE2) receptor poses a significant threat for viral emergence with pandemic potential. This review summarizes the approaches used to study binding interactions between CoV spike proteins and the human ACE2 (hACE2) receptor. Solid-phase enzyme immunoassays and cell binding assays allow qualitative assessment of binding but lack quantitative evaluation of affinity. Surface plasmon resonance, Bio-layer interferometry, and Microscale Thermophoresis on the other hand, provide accurate affinity measurement through equilibrium dissociation constants (K). modeling predicts affinity through binding structure modeling, protein-protein docking simulations, and binding energy calculations but reveals inconsistent results due to the lack of a standardized approach. Machine learning and deep learning models utilize simulated and experimental protein-protein interaction data to elucidate the critical residues associated with CoV binding affinity to hACE2. Further optimization and standardization of existing approaches for studying binding affinity could aid pandemic preparedness. Specifically, prioritizing surveillance of CoVs that can bind to human receptors stands to mitigate the risk of zoonotic spillover.
PubMed: 38304547
DOI: 10.1016/j.csbj.2024.01.009 -
BioRxiv : the Preprint Server For... Dec 2023The μ-opioid receptor (μOR), a prototypical member of the G protein-coupled receptor (GPCR) family, is the molecular target of opioid analgesics such as morphine and...
The μ-opioid receptor (μOR), a prototypical member of the G protein-coupled receptor (GPCR) family, is the molecular target of opioid analgesics such as morphine and fentanyl. Due to the limitations and severe side effects of currently available opioid drugs, there is considerable interest in developing novel modulators of μOR function. Most GPCR ligands today are small molecules, however biologics, including antibodies and nanobodies, are emerging as alternative therapeutics with clear advantages such as affinity and target selectivity. Here, we describe the nanobody NbE, which selectively binds to the μOR and acts as an antagonist. We functionally characterize NbE as an extracellular and genetically encoded μOR ligand and uncover the molecular basis for μOR antagonism by solving the cryo-EM structure of the NbE-μOR complex. NbE displays a unique ligand binding mode and achieves μOR selectivity by interactions with the orthosteric pocket and extracellular receptor loops. Based on a β-hairpin loop formed by NbE that deeply inserts into the μOR and centers most binding contacts, we design short peptide analogues that retain μOR antagonism. The work illustrates the potential of nanobodies to uniquely engage with GPCRs and describes novel μOR ligands that can serve as a basis for therapeutic developments.
PubMed: 38106026
DOI: 10.1101/2023.12.06.570395 -
Biochemical Pharmacology Nov 2023The renin-angiotensin system (RAS) comprises a broad set of functional peptides and receptors that play a role in cardiovascular homeostasis and contribute to... (Review)
Review
The renin-angiotensin system (RAS) comprises a broad set of functional peptides and receptors that play a role in cardiovascular homeostasis and contribute to cardiovascular pathologies. Angiotensin II (Ang II) is the most potent peptide hormone produced by the RAS due to its high abundance and its strong and pleiotropic impact on the cardiovascular system. Formation of Ang II takes place in the bloodstream and additionally in tissues in the so-called local RAS. Of the two Ang II receptors (AT1 and AT2) that Ang II binds to, AT1 is the most expressed throughout the mammalian body. AT1 expression is not restricted to cells of the cardiovascular system but in fact AT1 protein is found in nearly all organs, hence, Ang II takes part in several modulatory physiological processes one of which is erythropoiesis. In this review, we present multiple evidence supporting that Ang II modulates physiological and pathological erythropoiesis processes trough the AT1 receptor. Cumulative evidence indicates that Ang II by three distinct mechanisms influences erythropoiesis: 1) stimulation of renal erythropoietin synthesis; 2) direct action on bone marrow precursor cells; and 3) modulation of sympathetic nerve activity to the bone marrow. The text highlights clinical and preclinical evidence focusing on mechanistic studies using rodent models.
Topics: Animals; Receptor, Angiotensin, Type 1; Erythropoiesis; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Angiotensin II; Mammals
PubMed: 37714274
DOI: 10.1016/j.bcp.2023.115805 -
Nature Communications Oct 2023Histamine is a biogenic amine that participates in allergic and inflammatory processes by stimulating histamine receptors. The histamine H receptor (HR) is a potential...
Histamine is a biogenic amine that participates in allergic and inflammatory processes by stimulating histamine receptors. The histamine H receptor (HR) is a potential therapeutic target for chronic inflammatory diseases such as asthma and atopic dermatitis. Here, we show the cryo-electron microscopy structures of the HR-G complex bound with an endogenous agonist histamine or the selective agonist imetit bound in the orthosteric binding pocket. The structures demonstrate binding mode of histamine agonists and that the subtype-selective agonist binding causes conformational changes in Phe344, which, in turn, form the "aromatic slot". The results provide insights into the molecular underpinnings of the agonism of HR and subtype selectivity of histamine receptors, and show that the HR structures may be valuable in rational drug design of drugs targeting the HR.
Topics: Humans; Histamine; Receptors, Histamine H4; Cryoelectron Microscopy; Receptors, G-Protein-Coupled; Receptors, Histamine; Histamine Agonists
PubMed: 37863901
DOI: 10.1038/s41467-023-42260-z -
Proceedings of the National Academy of... Oct 2023Glucose-dependent insulinotropic polypeptide receptor (GIPR) is a potential drug target for metabolic disorders. It works with glucagon-like peptide-1 receptor and...
Glucose-dependent insulinotropic polypeptide receptor (GIPR) is a potential drug target for metabolic disorders. It works with glucagon-like peptide-1 receptor and glucagon receptor in humans to maintain glucose homeostasis. Unlike the other two receptors, GIPR has at least 13 reported splice variants (SVs), more than half of which have sequence variations at either C or N terminus. To explore their roles in endogenous peptide-mediated GIPR signaling, we determined the cryoelectron microscopy (cryo-EM) structures of the two N terminus-altered SVs (referred as GIPR-202 and GIPR-209 in the Ensembl database, SV1 and SV2 here, respectively) and investigated the outcome of coexpressing each of them in question with GIPR in HEK293T cells with respect to ligand binding, receptor expression, cAMP (adenosine 3,5-cyclic monophosphate) accumulation, β-arrestin recruitment, and cell surface localization. It was found that while both N terminus-altered SVs of GIPR neither bound to the hormone nor elicited signal transduction per se, they suppressed ligand binding and cAMP accumulation of GIPR. Meanwhile, SV1 reduced GIPR-mediated β-arrestin 2 responses. The cryo-EM structures of SV1 and SV2 showed that they reorganized the extracellular halves of transmembrane helices 1, 6, and 7 and extracellular loops 2 and 3 to adopt a ligand-binding pocket-occupied conformation, thereby losing binding ability to the peptide. The results suggest a form of signal bias that is constitutive and ligand-independent, thus expanding our knowledge of biased signaling beyond pharmacological manipulation (i.e., ligand specific) as well as constitutive and ligand-independent (e.g., SV1 of the growth hormone-releasing hormone receptor).
Topics: Humans; Gastric Inhibitory Polypeptide; Ligands; Cryoelectron Microscopy; HEK293 Cells; Signal Transduction; Receptors, Gastrointestinal Hormone; Peptides; Glucagon-Like Peptide-1 Receptor
PubMed: 37792509
DOI: 10.1073/pnas.2306145120 -
Neural Regeneration Research Dec 2023Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules... (Review)
Review
Axonal growth inhibitors are released during traumatic injuries to the adult mammalian central nervous system, including after spinal cord injury. These molecules accumulate at the injury site and form a highly inhibitory environment for axonal regeneration. Among these inhibitory molecules, myelin-associated inhibitors, including neurite outgrowth inhibitor A, oligodendrocyte myelin glycoprotein, myelin-associated glycoprotein, chondroitin sulfate proteoglycans and repulsive guidance molecule A are of particular importance. Due to their inhibitory nature, they represent exciting molecular targets to study axonal inhibition and regeneration after central injuries. These molecules are mainly produced by neurons, oligodendrocytes, and astrocytes within the scar and in its immediate vicinity. They exert their effects by binding to specific receptors, localized in the membranes of neurons. Receptors for these inhibitory cues include Nogo receptor 1, leucine-rich repeat, and Ig domain containing 1 and p75 neurotrophin receptor/tumor necrosis factor receptor superfamily member 19 (that form a receptor complex that binds all myelin-associated inhibitors), and also paired immunoglobulin-like receptor B. Chondroitin sulfate proteoglycans and repulsive guidance molecule A bind to Nogo receptor 1, Nogo receptor 3, receptor protein tyrosine phosphatase σ and leucocyte common antigen related phosphatase, and neogenin, respectively. Once activated, these receptors initiate downstream signaling pathways, the most common amongst them being the RhoA/ROCK signaling pathway. These signaling cascades result in actin depolymerization, neurite outgrowth inhibition, and failure to regenerate after spinal cord injury. Currently, there are no approved pharmacological treatments to overcome spinal cord injuries other than physical rehabilitation and management of the array of symptoms brought on by spinal cord injuries. However, several novel therapies aiming to modulate these inhibitory proteins and/or their receptors are under investigation in ongoing clinical trials. Investigation has also been demonstrating that combinatorial therapies of growth inhibitors with other therapies, such as growth factors or stem-cell therapies, produce stronger results and their potential application in the clinics opens new venues in spinal cord injury treatment.
PubMed: 37449592
DOI: 10.4103/1673-5374.373674 -
Proceedings of the National Academy of... Mar 2024Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been detected in almost all organs of coronavirus disease-19 patients, although some organs do...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been detected in almost all organs of coronavirus disease-19 patients, although some organs do not express angiotensin-converting enzyme-2 (ACE2), a known receptor of SARS-CoV-2, implying the presence of alternative receptors and/or co-receptors. Here, we show that the ubiquitously distributed human transferrin receptor (TfR), which binds to diferric transferrin to traffic between membrane and endosome for the iron delivery cycle, can ACE2-independently mediate SARS-CoV-2 infection. Human, not mouse TfR, interacts with Spike protein with a high affinity (K ~2.95 nM) to mediate SARS-CoV-2 endocytosis. TfR knock-down (TfR-deficiency is lethal) and overexpression inhibit and promote SARS-CoV-2 infection, respectively. Humanized TfR expression enables SARS-CoV-2 infection in baby hamster kidney cells and C57 mice, which are known to be insusceptible to the virus infection. Soluble TfR, Tf, designed peptides blocking TfR-Spike interaction and anti-TfR antibody show significant anti-COVID-19 effects in cell and monkey models. Collectively, this report indicates that TfR is a receptor/co-receptor of SARS-CoV-2 mediating SARS-CoV-2 entry and infectivity by likely using the TfR trafficking pathway.
Topics: Animals; Humans; Mice; Angiotensin-Converting Enzyme 2; COVID-19; Peptidyl-Dipeptidase A; Protein Binding; Receptors, Transferrin; SARS-CoV-2; Spike Glycoprotein, Coronavirus
PubMed: 38408250
DOI: 10.1073/pnas.2317026121