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- Nitrite protects neurons against hypoxic damage through <i>S</i>-nitrosylation of caspase-6. [Journal Article]
- ARAntioxid Redox Signal 2018 Nov 12
- CONCLUSIONS: Our findings suggest that nitrite holds great potential for the treatment of diseases such as COPD associated with hypoxia-induced neuronal injury.
- Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1. [Journal Article]
- SStructure 2018 Oct 25
- Nuclear receptor-related 1 protein (Nurr1/NR4A2) is an orphan nuclear receptor (NR) that is considered to function without a canonical ligand-binding pocket (LBP). A crystal structure of the Nurr1 li...
Nuclear receptor-related 1 protein (Nurr1/NR4A2) is an orphan nuclear receptor (NR) that is considered to function without a canonical ligand-binding pocket (LBP). A crystal structure of the Nurr1 ligand-binding domain (LBD) revealed no physical space in the conserved region where other NRs with solvent accessible apo-protein LBPs bind synthetic and natural ligands. Using solution nuclear magnetic resonance spectroscopy, hydrogen/deuterium exchange mass spectrometry, and molecular dynamics simulations, we show that the putative canonical Nurr1 LBP is dynamic with high solvent accessibility, exchanges between two or more conformations on the microsecond-to-millisecond timescale, and can expand from the collapsed crystallized conformation to allow binding of unsaturated fatty acids. These findings should stimulate future studies to probe the ligandability and druggability of Nurr1 for both endogenous and synthetic ligands, which could lead to new therapeutics for Nurr1-related diseases, including Parkinson's disease and schizophrenia.
- Effects of short term hypothyroidism on the lipid transfer to HDL and other parameters related to lipoprotein metabolism in patients submitted to thyroidectomy for thyroid cancer. [Journal Article]
- TThyroid 2018 Nov 09
- CONCLUSIONS: In short-term hypothyroidism, HDL-cholesterol increased but this did not increase the capacity of the HDL fraction to receive lipids or the activity of PON-1, the anti-oxidation enzyme associated to HDL.
- Screening and Identification of Pregnancy Zone Protein (PZP) and Leucine-Rich Alpha-2-Glycoprotein (LRG) as Potential Serum Biomarkers for Early-onset Myocardial Infarction using Protein Profile Analysis. [Journal Article]
- PCProteomics Clin Appl 2018 Nov 08; :e1800079
- CONCLUSIONS: We identified five differential serum proteins in early-onset MI using proteomic analysis. Lipoprotein-related biomarkers further demonstrate the close relationship between lipid metabolism and the disease. Inflammation-associated LRG and PZP may be novel biomarkers of the disease. In addition, changes in these proteins may partly reveal the possible mechanisms in the pathogenesis and pathophysiology of early-onset MI. This article is protected by copyright. All rights reserved.
- β-amyloid wall deposit of temporal artery in subjects with spontaneous intracerebral haemorrhage. [Journal Article]
- OOncotarget 2018 Oct 05; 9(78):34699-34707
- Cerebral Amyloid Angiopathy has been indicated as an important cause of spontaneous non-hypertensive intracerebral haemorrhage (ICH).
Cerebral Amyloid Angiopathy has been indicated as an important cause of spontaneous non-hypertensive intracerebral haemorrhage (ICH).
- Molecular Dynamics Simulations Reveal Differentiated Context-Dependent Conformational Dynamics of Two Proteins of the Same Family. [Journal Article]
- JPJ Phys Chem B 2018 Nov 08
- The Arabidopsis pyrabactin resistant 1 (PYR1)-like family of proteins (PYLs) are receptors of abscisic acid (ABA), an essential small signaling molecule in plants. Here we report a comparative molecu...
The Arabidopsis pyrabactin resistant 1 (PYR1)-like family of proteins (PYLs) are receptors of abscisic acid (ABA), an essential small signaling molecule in plants. Here we report a comparative molecular dynamics (MD) study on two PYL members, PYR1 and PYL10, which, despite their highly similar sequences and structures, have been suggested to belong to two different subclasses of PYLs, one being dimeric and relying on binding to ABA to inhibit downstream type 2C protein phosphatases (PP2Cs), the other being monomeric and able to constitutively inhibit downstream PP2Cs without ABA. MD simulations have been carried out on these proteins in various monomeric or complexation states. Analyses of the simulations unambiguously confirm that ABA has large effects on the conformational dynamics of PYR1 but not PYL10, while a downstream PP2C has much larger effects on PYL10 than on PYR1. The differentiated effects are consistent with the functional differences between the two proteins. Potential of mean forces (PMF) calculated by umbrella sampling showed that binding to ABA strengthens the PYR1-PP2C complex, increasing the PMF change for dissociation from 7.5 to 12.0 kcal mol-1. On the other hand, the same PMF change for an apo-PYL10-PP2C complex was computed to be 9.5 kcal mol-1, suggesting stronger binding in apo-PYL10-PP2C than in apo-PYR1-PP2C. Several specific sequence features that may contribute to the functional differentiation between PYR1 and PYL10 are suggested based on the inter-subunit residue-residue contacts occurred in the simulations.
- An efficient use of X-Ray information, Homology Modeling, Molecular Dynamics and Knowledge-based Docking techniques to predict Protein-monosaccharide complexes. [Journal Article]
- GGlycobiology 2018 Nov 08
- Unraveling the structure of lectin-carbohydrate complexes is vital for understanding key biological recognition processes and development of glycomimetic drugs. Molecular Docking application to predi...
Unraveling the structure of lectin-carbohydrate complexes is vital for understanding key biological recognition processes and development of glycomimetic drugs. Molecular Docking application to predict them is challenging due to their low affinity, hydrophilic nature and ligand conformational diversity. In the last decade several strategies, such as the inclusion of glycan conformation specific scoring functions or our developed solvent-site biased method, have improved carbohydrate docking performance but significant challenges remain, in particular, those related to receptor conformational diversity.In the present work we have analyzed conventional and solvent-site biased autodock4 performance concerning receptor conformational diversity as derived from different crystal structures (apo and holo), Molecular Dynamics snapshots and Homology-based models, for fourteen different lectin-monosaccharide complexes. Our results show that both conventional and biased docking yield accurate lectin-monosaccharide complexes, starting from either apo or homology-based structures, even when only moderate ( < 45%) sequence identity templates are available. An essential element for success is a proper combination of a middle-sized (10-100 structures) conformational ensemble, derived either from Molecular dynamics or multiple homology model building. Consistent with our previous works, results show that solvent-site biased methods improve overall performance, but that results are still highly system dependent. Finally, our results also show that docking can select the correct receptor structure within the ensemble, underscoring the relevance of joint evaluation of both ligand pose and receptor conformation.
- Tonicity inversely modulates lipocalin-2 (Lcn2/24p3/NGAL) receptor (SLC22A17) and Lcn2 expression via Wnt/β-catenin signaling in renal inner medullary collecting duct cells: implications for cell fate and bacterial infection. [Journal Article]
- CCCell Commun Signal 2018 Nov 07; 16(1):74
- CONCLUSIONS: Lcn2-R upregulation and Lcn2 downregulation via Wnt/β-catenin may promote adaptive osmotolerant survival of IMCD cells in response to hyperosmolarity/-tonicity whereas Lcn2 upregulation and Lcn2-R downregulation via TLR-4 and/or normosmolarity/-tonicity may protect IMCD cells against bacterial infections and prevent autocrine death induction by Lcn2.
- Triglyceride-Rich Lipoproteins and Novel Targets for Anti-atherosclerotic Therapy. [Review]
- KCKorean Circ J 2018; 48(12):1097-1119
- Although elevated serum low-density lipoprotein-cholesterol (LDL-C) is without any doubts accepted as an important risk factor for cardiovascular disease (CVD), the role of elevated triglycerides (TG...
Although elevated serum low-density lipoprotein-cholesterol (LDL-C) is without any doubts accepted as an important risk factor for cardiovascular disease (CVD), the role of elevated triglycerides (TGs)-rich lipoproteins as an independent risk factor has until recently been quite controversial. Recent data strongly suggest that elevated TG-rich lipoproteins are an independent risk factor for CVD and that therapeutic targeting of them could possibly provide further benefit in reducing CVD morbidity, events and mortality, apart from LDL-C lowering. Today elevated TGs are treated with lifestyle interventions, and with fibrates which could be combined with omega-3 fatty acids. There are also some new drugs. Volanesorsen, is an antisense oligonucleotid that inhibits the production of the Apo C-III which is crucial in regulating TGs metabolism because it inhibits lipoprotein lipase (LPL) and hepatic lipase activity but also hepatic uptake of TGs-rich particles. Evinacumab is a monoclonal antibody against angiopoietin-like protein 3 (ANGPTL3) and it seems that it can substantially lower elevated TGs levels because ANGPTL3 also regulates TGs metabolism. Pemafibrate is a selective peroxisome proliferator-activated receptor alpha modulator which also decreases TGs, and improves other lipid parameters. It seems that it also has some other possible antiatherogenic effects. Alipogene tiparvovec is a nonreplicating adeno-associated viral vector that delivers copies of the LPL gene to muscle tissue which accelerates the clearance of TG-rich lipoproteins thus decreasing extremely high TGs levels. Pradigastat is a novel diacylglycerol acyltransferase 1 inhibitor which substantially reduces extremely high TGs levels and appears to be promising in treatment of the rare familial chylomicronemia syndrome.
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- Cryo-EM reveals two distinct serotonin-bound conformations of full-length 5-HT3A receptor. [Journal Article]
- NatNature 2018; 563(7730):270-274
- The 5-HT3A serotonin receptor1, a cationic pentameric ligand-gated ion channel (pLGIC), is the clinical target for management of nausea and vomiting associated with radiation and chemotherapies2. Upo...
The 5-HT3A serotonin receptor1, a cationic pentameric ligand-gated ion channel (pLGIC), is the clinical target for management of nausea and vomiting associated with radiation and chemotherapies2. Upon binding, serotonin induces a global conformational change that encompasses the ligand-binding extracellular domain (ECD), the transmembrane domain (TMD) and the intracellular domain (ICD), the molecular details of which are unclear. Here we present two serotonin-bound structures of the full-length 5-HT3A receptor in distinct conformations at 3.32 Å and 3.89 Å resolution that reveal the mechanism underlying channel activation. In comparison to the apo 5-HT3A receptor, serotonin-bound states underwent a large twisting motion in the ECD and TMD, leading to the opening of a 165 Å permeation pathway. Notably, this motion results in the creation of lateral portals for ion permeation at the interface of the TMD and ICD. Combined with molecular dynamics simulations, these structures provide novel insights into conformational coupling across domains and functional modulation.