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Arthritis Research 2002It is not known to what extent glucocorticoid hormones cause their anti-inflammatory actions and their undesirable side effects by the same or different molecular... (Review)
Review
It is not known to what extent glucocorticoid hormones cause their anti-inflammatory actions and their undesirable side effects by the same or different molecular mechanisms. Glucocorticoids combine with a cytoplasmic receptor that alters gene expression in two ways. One way is dependent on the receptor's binding directly to DNA and acting (positively or negatively) as a transcription factor. The other is dependent on its binding to and interfering with other transcription factors. Both mechanisms could underlie suppression of inflammation. The liganded receptor binds and inhibits the inflammatory transcription factors activator protein-1 and NF-kappaB. It also directly induces anti-inflammatory genes such as that encoding the protein inhibitor of NF-kappaB. Recent work has shown that glucocorticoids inhibit signalling in the mitogen-activated protein kinase pathways that mediate the expression of inflammatory genes. This inhibition is dependent on de novo gene expression. It is important to establish the significance of these different mechanisms for the various physiological effects of glucocorticoids, because it may be possible to produce steroid-related drugs that selectively target the inflammatory process.
Topics: Anti-Inflammatory Agents; Dexamethasone; Enzyme Inhibitors; Glucocorticoids; Humans; Inflammation; Mitogen-Activated Protein Kinases; Receptors, Glucocorticoid; Signal Transduction; Transcription Factors
PubMed: 12010562
DOI: 10.1186/ar398 -
The International Journal of... Feb 2000Fibroblast growth factor-2 (FGF-2) is a member of a large family of proteins that bind heparin and heparan sulfate and modulate the function of a wide range of cell... (Review)
Review
Fibroblast growth factor-2 (FGF-2) is a member of a large family of proteins that bind heparin and heparan sulfate and modulate the function of a wide range of cell types. FGF-2 stimulates the growth and development of new blood vessels (angiogenesis) that contribute to the pathogenesis of several diseases (i.e. cancer, atherosclerosis), normal wound healing and tissue development. FGF-2 contains a number of basic residues (pI 9.6) and consists of 12 anti-parallel beta-sheets organized into a trigonal pyrimidal structure. FGF-2 binds to four cell surface receptors expressed as a number of splice variants. Many of the biological activities of FGF-2 have been found to depend on its receptor's intrinsic tyrosine kinase activity and second messengers such as the mitogen activated protein kinases. However, considerable evidence suggest that intracellular FGF-2 might have a direct biological role particularly within the nucleus. In addition, heparan sulfate proteoglycans have been demonstrated to enhance and inhibit FGF-2 activity. The possibility that FGF-2 activity can be manipulated through alterations in heparan sulfate-binding is currently being exploited in the development of clinical applications aimed at modulating either endogenous or administered FGF-2 activity.
Topics: Animals; Fibroblast Growth Factor 2; Heparan Sulfate Proteoglycans; Heparin; Heparitin Sulfate; Humans; Models, Biological; Models, Molecular; Protein Conformation; Signal Transduction
PubMed: 10687947
DOI: 10.1016/s1357-2725(99)00123-5 -
Biophysical Reviews Dec 2022Multicanonical molecular dynamics (McMD)-based dynamic docking is a powerful tool to not only predict the native binding configuration between two flexible molecules,... (Review)
Review
UNLABELLED
Multicanonical molecular dynamics (McMD)-based dynamic docking is a powerful tool to not only predict the native binding configuration between two flexible molecules, but it can also be used to accurately simulate the binding/unbinding pathway. Furthermore, it can also predict alternative binding sites, including allosteric ones, by employing an exhaustive sampling approach. Since McMD-based dynamic docking accurately samples binding/unbinding events, it can thus be used to determine the molecular mechanism of binding between two molecules. We developed the McMD-based dynamic docking methodology based on the powerful, but woefully underutilized McMD algorithm, combined with a toolset to perform the docking and to analyze the results. Here, we showcase three of our recent works, where we have applied McMD-based dynamic docking to advance the field of computational drug design. In the first case, we applied our method to perform an exhaustive search between Hsp90 and one of its inhibitors to successfully predict the native binding configuration in its binding site, as we refined our analysis methods. For our second case, we performed an exhaustive search of two medium-sized ligands and Bcl-xL, which has a cryptic binding site that differs greatly between the apo and holo structures. Finally, we performed a dynamic docking simulation between a membrane-embedded GPCR molecule and a high affinity ligand that binds deep within its receptor's pocket. These advanced simulations showcase the power that the McMD-based dynamic docking method has, and provide a glimpse of the potential our methodology has to unravel and solve the medical and biophysical issues in the modern world.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s12551-022-01010-z.
PubMed: 36659995
DOI: 10.1007/s12551-022-01010-z -
Journal of Innate Immunity 2009The interactions between Mycobacterium tuberculosis and host phagocytes such as macrophages and dendritic cells are central to both immunity and pathogenesis. Many... (Review)
Review
The interactions between Mycobacterium tuberculosis and host phagocytes such as macrophages and dendritic cells are central to both immunity and pathogenesis. Many receptors have been implicated in recognition and binding of M. tuberculosis such as the mannose receptor, dendritic-cell-specific intercellular adhesion molecule-3 grabbing nonintegrin, dectin-1 and complement receptor 3 as well as Toll-like receptors, scavenger receptors and CD14. While in vitro studies have demonstrated clear roles for particular receptor(s), in vivo work in receptor-deficient animals often revealed only a minor, or no role, in infection with M. tuberculosis. The initial encounter of phagocytic cells with myco- bacteria appears to be complex and depends on various parameters. It seems likely that infection with M. tuberculosis does not occur via a single receptor-mediated pathway. Rather, multiple receptors play different roles in M. tuberculosis infection, and the overall effect depends on the expression and availability of a particular receptor on a particular cell type and its triggered downstream responses. Moreover, the role of membrane cholesterol for M. tuberculosis interactions with phagocytes adds to the complexity of mycobacterial recognition and response. This review summarizes current knowledge on non-opsonic receptors involved in binding of mycobacteria and discusses the contribution of individual receptors to the recognition process.
Topics: Dendritic Cells; Humans; Immunity, Innate; Macrophages; Mycobacterium tuberculosis; Phagocytes; Receptors, Immunologic; Tuberculosis
PubMed: 20375581
DOI: 10.1159/000173703 -
Cellular and Molecular Life Sciences :... Mar 2023Membrane trafficking processes regulate the G protein-coupled receptor activity. The muscarinic acetylcholine receptors (mAChRs) are highly pursued drug targets for...
Membrane trafficking processes regulate the G protein-coupled receptor activity. The muscarinic acetylcholine receptors (mAChRs) are highly pursued drug targets for neurological diseases, but the cellular machineries that control the trafficking of these receptors remain largely elusive. Here, we revealed the role of the small GTPase Rab10 as a negative regulator for the post-activation trafficking of M4 mAChR and the underlying mechanism. We show that constitutively active Rab10 arrests the receptor within Rab5-positive early endosomes and significantly hinders the resensitization of M4-mediated Ca signaling. Mechanistically, M4 binds to Rab10-GTP, which requires the motif RKKRQMAA (R-A) within the third intracellular loop. Moreover, Rab10-GTP inactivates Arf6 by recruiting the Arf6 GTPase-activating protein, ACAP1. Strikingly, deletion of the motif R-A causes M4 to bypass the control by Rab10 and switch to the Rab4-facilitated fast recycling pathway, thus reusing the receptor. Therefore, Rab10 couples the cargo sorting and membrane trafficking regulation through cycle between GTP-bound and GDP-bound state. Our findings suggest a model that Rab10 binds to the M4 like a molecular brake and controls the receptor's transport through endosomes, thus modulating the signaling, and this regulation is specific among the mAChR subtypes.
Topics: GTP Phosphohydrolases; Cell Membrane; Receptors, Muscarinic; Signal Transduction; Endosomes; Carrier Proteins; Guanosine Triphosphate; rab GTP-Binding Proteins
PubMed: 36917255
DOI: 10.1007/s00018-023-04722-x -
Cold Spring Harbor Perspectives in... Aug 2015Entry of hepatitis B (HBV) and hepatitis D viruses (HDV) into a host cell represents the initial step of infection. This process requires multiple steps, including the... (Review)
Review
Entry of hepatitis B (HBV) and hepatitis D viruses (HDV) into a host cell represents the initial step of infection. This process requires multiple steps, including the low-affinity attachment of the virus to the cell surface, followed by high-affinity attachment to specific receptor(s), and subsequent endocytosis-mediated internalization. Within the viral envelope, the preS1 region is involved in receptor binding. Recently, sodium taurocholate cotransporting polypeptide (NTCP) has been identified as an entry receptor of HBV and HDV by affinity purification using a preS1 peptide. NTCP is mainly or exclusively expressed in the liver, and this membrane protein is at least one of the factors determining the narrow species specificity and hepatotropism of HBV and HDV. However, there are likely other factors that mediate the species and tissue tropism of HBV. This review summarizes the current understanding of the mechanisms of HBV/HDV entry.
Topics: Female; Hepatitis B; Hepatitis B virus; Hepatitis D; Hepatitis Delta Virus; Humans; Male; Receptors, Virus; Species Specificity; Taurocholic Acid; Tropism; Viral Envelope Proteins; Virion; Virus Internalization
PubMed: 26238794
DOI: 10.1101/cshperspect.a021378 -
Kidney International Apr 2000Aldosterone exerts its biological effects through binding to mineralocorticoid receptor (MR). Ligand binding induces a receptor transconformation within the... (Review)
Review
Aldosterone exerts its biological effects through binding to mineralocorticoid receptor (MR). Ligand binding induces a receptor transconformation within the ligand-binding domain and dissociation of associated proteins from the receptor. The ligand-activated receptor binds as a dimer to the response elements present in the promoter region of target genes and initiates the transcription through specific interactions with the transcription machinery. The glucocorticoid hormone cortisol binds to the human MR (hMR) with the same affinity as aldosterone, but is less efficient than aldosterone in stimulating the hMR transactivation. The antimineralocorticoid spirolactones also bind to the hMR but induce a receptor conformation that is transcriptionally silent. In this report, we describe the key residues involved in the recognition of agonist and antagonist ligands and propose a two-step model with a dynamic dimension for the MR activation. In its unliganded state, MR is in an opened conformation in which folding into the ligand-binding competent state requires both the heat shock protein 90 and the C-terminal part of the receptor. An intermediate complex is generated by ligand binding, leading to a more compact receptor conformation. This transient complex is then converted to a transcriptionally active conformation in which stability depends on the steroid-receptor contacts.
Topics: Amino Acids; Humans; Ligands; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Protein Folding; Receptors, Mineralocorticoid
PubMed: 10760050
DOI: 10.1046/j.1523-1755.2000.00958.x -
ENeuro 2021Secreted amyloid-β (Aβ) peptide forms neurotoxic oligomeric assemblies thought to cause synaptic deficits associated with Alzheimer's disease (AD). Soluble Aβ...
Secreted amyloid-β (Aβ) peptide forms neurotoxic oligomeric assemblies thought to cause synaptic deficits associated with Alzheimer's disease (AD). Soluble Aβ oligomers (Aβo) directly bind to neurons with high affinity and block plasticity mechanisms related to learning and memory, trigger loss of excitatory synapses and eventually cause cell death. While Aβo toxicity has been intensely investigated, it remains unclear precisely where Aβo initially binds to the surface of neurons and whether sites of binding relate to synaptic deficits. Here, we used a combination of live cell, super-resolution and ultrastructural imaging techniques to investigate the kinetics, reversibility and nanoscale location of Aβo binding. Surprisingly, Aβo does not bind directly at the synaptic cleft as previously thought but, instead, forms distinct nanoscale clusters encircling the postsynaptic membrane with a significant fraction also binding presynaptic axon terminals. Synaptic plasticity deficits were observed at Aβo-bound synapses but not closely neighboring Aβo-free synapses. Thus, perisynaptic Aβo binding triggers spatially restricted signaling mechanisms to disrupt synaptic function. These data provide new insight into the earliest steps of Aβo pathology and lay the groundwork for future studies evaluating potential surface receptor(s) and local signaling mechanisms responsible for Aβo binding and synapse dysfunction.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Humans; Neuronal Plasticity; Neurons; Synapses
PubMed: 34789478
DOI: 10.1523/ENEURO.0416-21.2021 -
Current Opinion in Virology Dec 2013The feline and human immunodeficiency viruses (FIV and HIV) target helper T cells selectively, and in doing so they induce a profound immune dysfunction. The primary... (Review)
Review
The feline and human immunodeficiency viruses (FIV and HIV) target helper T cells selectively, and in doing so they induce a profound immune dysfunction. The primary determinant of HIV cell tropism is the expression pattern of the primary viral receptor CD4 and co-receptor(s), such as CXCR4 and CCR5. FIV employs a distinct strategy to target helper T cells; a high affinity interaction with CD134 (OX40) is followed by binding of the virus to its sole co-receptor, CXCR4. Recent studies have demonstrated that the way in which FIV interacts with its primary receptor, CD134, alters as infection progresses, changing the cell tropism of the virus. This review examines the contribution of the virus-receptor interaction to replication in vivo as well as the significance of these findings to the development of vaccines and therapeutics.
Topics: Animals; Cats; Host-Pathogen Interactions; Immunodeficiency Virus, Feline; Receptors, CXCR4; Receptors, OX40; Receptors, Virus; T-Lymphocytes; Viral Tropism; Virus Attachment
PubMed: 23992667
DOI: 10.1016/j.coviro.2013.08.003 -
Anesthesiology Nov 2018WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Naphthalene-etomidate, an etomidate analog containing a bulky phenyl ring substituent group, possesses very low...
WHAT WE ALREADY KNOW ABOUT THIS TOPIC
WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Naphthalene-etomidate, an etomidate analog containing a bulky phenyl ring substituent group, possesses very low γ-aminobutyric acid type A (GABAA) receptor efficacy and acts as an anesthetic-selective competitive antagonist. Using etomidate analogs containing phenyl ring substituents groups that range in volume, we tested the hypothesis that this unusual pharmacology is caused by steric hindrance that reduces binding to the receptor's open state.
METHODS
The positive modulatory potencies and efficacies of etomidate and phenyl ring-substituted etomidate analogs were electrophysiology defined in oocyte-expressed α1β3γ2L GABAA receptors. Their binding affinities to the GABAA receptor's two classes of transmembrane anesthetic binding sites were assessed from their abilities to inhibit receptor labeling by the site-selective photolabels [H]azi-etomidate and tritiated R-5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl) barbituric acid.
RESULTS
The positive modulatory activities of etomidate and phenyl ring-substituted etomidate analogs progressively decreased with substituent group volume, reflecting significant decreases in both potency (P = 0.005) and efficacy (P < 0.0001). Affinity for the GABAA receptor's two β - α anesthetic binding sites similarly decreased with substituent group volume (P = 0.003), whereas affinity for the receptor's α - β/γ - β sites did not (P = 0.804). Introduction of the N265M mutation, which is located at the β - α binding sites and renders GABAA receptors etomidate-insensitive, completely abolished positive modulation by naphthalene-etomidate.
CONCLUSIONS
Steric hindrance selectively reduces phenyl ring-substituted etomidate analog binding affinity to the two β - α anesthetic binding sites on the GABAA receptor's open state, suggesting that the binding pocket where etomidate's phenyl ring lies becomes smaller as the receptor isomerizes from closed to open.
Topics: Anesthetics, Intravenous; Animals; Cell Culture Techniques; Etomidate; Humans; Oocytes; Receptors, GABA; Xenopus
PubMed: 30052529
DOI: 10.1097/ALN.0000000000002356