modulated structure
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Cellobiose dehydrogenase (CDH) from wood degrading fungi represents a subclass of oxidoreductases with unique properties. Consisting of two domains exhibiting interdomain electron transfer, this is the only known flavocytochrome involved in wood degradation. High resolution structures of the separated domains were solved, but the overall architecture of the intact protein and the exact interface of the two domains is unknown. Recently, it was shown that divalent cations modulate the activity of CDH and its pH optimum and a possible mechanism involving bridging of negative charges by calcium ions was proposed. Here we provide a structural explanation of this phenomenon confirming the interaction between negatively charged surface patches and calcium ions at the domain interface.
Nikotinový acetylcholinový receptor (nAChR) je ligandem řízený iontový kanál, který zprostředkuje neurotransmisi v cholinergním systému centrálním i periferním. Je tvořený komplexem pěti podjednotek, které patří podle své odlišné polypeptidové struktury do čtyřech skupin, označovaných a, b, g a d. Ve skupině a podjednotek bylo identifikováno ještě dalších devět podtypů (a1–9), ve skupině b čtyři (b1–4). Neuronální nAChR, nacházející se v různých oblastech mozku, jsou jednak pentamery heteromerní, sestávající z různých kombinací podjednotek a (a2–a6) s podjednotkami b (b2–b4), jednak homomerní, složené z pěti stejných podjednotek a (a7, a8, a9). Působí nejen na synapsích cholinergních neuronů, ale také – prostřednictvím presynaptické lokalizace na axonech jiných transmisních systémů – modulují uvolňování dalších neurotransmiterů (GABA, DA, NA, 5-HT, glutamát). Všechny tyto skutečnosti naznačují, že nAChRy mohou hrát významnou roli v zajištění optimální funkce CNS v regulaci komplexních procesů reakce organizmu (např. pozornost, chování, učení, paměť, adaptace apod.). Je podán přehled současných znalostí o funkci nAChRů a jejich podtypů v normě i v nemoci (Alzheimerova a Parkinsonova choroba, schizofrenie, deprese, autizmus, Tourettův syndrom) a diskutovány možnosti nových aspektů farmakoterapeutické strategie.
Nicotinic acetylcholine receptor (nAChR) is a ligand gated ion channel mediating neurotransmission in the cholinergic system both peripheral and central. It consists of five subunits which belong - according to differences of polypeptide structure – to four groups denoted a, b, g and d, with subunit a having 9 subtypes (a1–9), subunit b having 4 subtypes (b1–4). Neuronal nAChRs occuring in different brain regions are pentamers either heteromeric composed of various combinations of subunits a (a2–a6) with subunits b (b2–b4), or homomeric formed by five identical subunits a (a7, a8, a9). They act not only on the synapses of cholinergic neurons, but also – by means of presynaptic localization on axons of other transmission systems - modulate the release of additional neurotransmitters (GABA, DA, NA, 5-HT, glutamate). All these facts indicate that nAChRs may play a significant role in securing optimal CNS functions and in regulating intricate processes of individual reactivity (i.e. attention, behaviour, learning, memory, adaptation etc.). A review of recent knowledge is presented concerning the functions of nAChRs and their subtypes in norm and pathology (Alzheimer and Parkinson disease, schizophrenia, depression, autism, Tourette´s syndrom), and the possibilities of new aspects in pharmacotherapeutic strategy are discussed.
... Contents -- Protein Structure -- Part 1 Basic Structural Principles -- 1. ... ... Motifs of Protein Structure -- Few general principles emerged from the first protein structure -- The ... ... -- Topology diagrams are useful for classification of protein structures -- Secondary structure elements ... ... 72 -- The hemagglutinin polypeptide chain folds into a complex structure 72 -- The subunit structure ... ... is necessary for prediction of tertiary structure 251 -- Prediction methods for secondary structure ...
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SDF-1, nový cytokin z rodiny a-chemokinů, hraje klíčovou roli v regulaci hematopoézy. Vyskytuje se ve dvou formách (alfa a beta), které vznikají cestou alternativního splicingu. Jeho vysoká exprese v mikroprostředí kostní dřeně je zodpovědná za uvolňování progenitorových buněk do cirkulace a představuje prevenci nekontrolovaného úniku CD34+ buněk. Zvláště významná je jeho stimulace proliferace progenitorů B-řady, u ostatních krevních řad se projevuje jako senzibilizují faktor vůči jiným cytokinům. Schopnost indukovat agregaci trombocytů odhaluje roli SDF-1 v trombogenezi a obliteraci lumina cév postižených aterosklerózou. Výlučným receptorem pro SDF-1 je CXCR4, jehož přítomnost byla prokázána v řadě tkání a orgánů. Jejich přítomnost byla potvrzena i v mozkových tumorech, přičemž míra jejich exprese stoupá s gradingem, angiogenezí a výskytem nekrotických změn v tumoru. Díky této vlastnosti bude pravděpodobně možné určovat i prognózu pacientů. SDF-1 je také supresorem imunitní odpovědi skrze jeho facilitující účinek na interakci makrofágů s CD8+ T-lymfocyty. Afinita T-lymfocytotropního HIV k CXCR4 dává naději na možné ovlivnění infekce pomocí SDF-1. Význam SDF-1 a jeho receptoru CXCR4 potvrzují morfologické a funkční odchylky novorozených myší při jejich absenci, zvl. poruchy hematopoézy, angiogeneze a vývoje srdeční a nervové tkáně.
SDF-1, a novel cytokine from a-chemokine family, plays a key role in regulation of haematopoiesis. It exists in two forms (alpha and beta) that originate from alternative splicing. Its high expression in the bone marrow microenvironment accounts for the release of progenitor cells in the circulation and represents a prevention of uncontrolled leak of CD34+ cells. Notably significant is its stimulation of proliferation of B-lineage progenitors, in other haematopoietic lineages it functions as a facilitating factor of other cytokines. Ability of induction of platelet aggregation reveales the role of SDF-1 in thrombogenesis and vascular lumen obliteration in vessels affected by atherosclerosis. The only receptor for SDF-1 in thrombogenesis and vascular lumen obliteration in vessels affected by atherosclerosis. The only receptor for SDF-1 is CXCR, whose presence was proved in great numbers of tissues and organs. Their presence was also verified in brain tumours, whereas degree of their expression raises with grading, angiogenesis and occurrence of necrotic changes in tumour. Thanks to this feature it will probably be possible to estimate the prognosis of the patients. SDF-1 is also a suppressor of immune response via its facilitating activity on the interaction of the macrophages and CD8+ T lymphocytes. Affinity of the T-lymphocytotropic HIV to CXCR4 holds out hopes for a possible modulation of the infection with SDF-1. The significance of SDF-1 and its receptor CXCR4 is supported by morphological and functional abnormalities of new-born mice in their absence, especially disorders in haematopoiesis, angiogenesis and development of cardiac and nervous tissues.
Recent studies suggest CNNM2 (cyclin M2) to be part of the long-sought basolateral Mg2+ extruder at the renal distal convoluted tubule, or its regulator. In the present study, we explore structural features and ligand-binding capacities of the Bateman module of CNNM2 (residues 429-584), an intracellular domain structurally equivalent to the region involved in Mg2+ handling by the bacterial Mg2+ transporter MgtE, and AMP binding by the Mg2+ efflux protein CorC. Additionally, we studied the structural impact of the pathogenic mutation T568I located in this region. Our crystal structures reveal that nucleotides such as AMP, ADP or ATP bind at only one of the two cavities present in CNNM2429-584. Mg2+ favours ATP binding by alleviating the otherwise negative charge repulsion existing between acidic residues and the polyphosphate group of ATP. In crystals CNNM2429-584 forms parallel dimers, commonly referred to as CBS (cystathionine β-synthase) modules. Interestingly, nucleotide binding triggers a conformational change in the CBS module from a twisted towards a flat disc-like structure that mostly affects the structural elements connecting the Bateman module with the transmembrane region. We furthermore show that the T568I mutation, which causes dominant hypomagnesaemia, mimics the structural effect induced by nucleotide binding. The results of the present study suggest that the T568I mutation exerts its pathogenic effect in humans by constraining the conformational equilibrium of the CBS module of CNNM2, which becomes 'locked' in its flat form.
- MeSH
- cykliny chemie genetika metabolismus MeSH
- cystathionin-beta-synthasa chemie genetika metabolismus MeSH
- konformace proteinů MeSH
- krystalizace MeSH
- lidé MeSH
- molekulární sekvence - údaje MeSH
- mutace genetika MeSH
- nukleotidy chemie metabolismus MeSH
- sekundární struktura proteinů MeSH
- sekvence aminokyselin MeSH
- vazebná místa fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Here, we report the synthesis of pregn-5-ene and androst-5-ene dicarboxylic acid esters and explore the structure-activity relationship (SAR) for their modulation of N-methyl-d-aspartate receptors (NMDARs). All compounds were positive modulators of recombinant GluN1/GluN2B receptors (EC50 varying from 1.8 to 151.4 μM and Emax varying from 48% to 452%). Moreover, 10 compounds were found to be more potent GluN1/GluN2B receptor modulators than endogenous pregnenolone sulfate (EC50 = 21.7 μM). The SAR study revealed a relationship between the length of the residues at carbon C-3 of the steroid molecule and the positive modulatory effect at GluN1/GluN2B receptors for various D-ring modifications. A selected compound, 20-oxo-pregnenolone hemiadipate, potentiated native NMDARs to a similar extent as GluN1/GluN2A-D receptors and inhibited AMPARs and GABAAR responses. These results provide a unique opportunity for the development of new steroid based drugs with potential use in the treatment of neuropsychiatric disorders involving hypofunction of NMDARs.
- MeSH
- alosterická regulace MeSH
- HEK293 buňky MeSH
- konformace proteinů MeSH
- lidé MeSH
- modulátory membránového transportu chemie farmakologie MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- pregnenolon farmakologie MeSH
- receptory N-methyl-D-aspartátu antagonisté a inhibitory metabolismus MeSH
- steroidy chemie farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The glycocalyx of the endothelium is an intravascular compartment that creates a barrier between circulating blood and the vessel wall. The glycocalyx is suggested to play an important role in numerous physiological processes including the regulation of vascular permeability, the prevention of the margination of blood cells to the vessel wall, and the transmission of shear stress. Various theoretical models and experimental approaches provide data about changes to the structure and functions of the glycocalyx under various types of inflammatory conditions. These alterations are suggested to promote inflammatory processes in vessels and contribute to the pathogenesis of number of diseases. In this review we summarize current knowledge about the modulation of the glycocalyx under inflammatory conditions and the consequences for the course of inflammation in vessels. The structure and functions of endothelial glycocalyx are briefly discussed in the context of methodological approaches regarding the determination of endothelial glycocalyx and the uncertainty and challenges involved in glycocalyx structure determination. In addition, the modulation of glycocalyx structure under inflammatory conditions and the possible consequences for pathogenesis of selected diseases and medical conditions (in particular, diabetes, atherosclerosis, ischemia/reperfusion, and sepsis) are summarized. Finally, therapeutic strategies to ameliorate glycocalyx dysfunction suggested by various authors are discussed.
- MeSH
- cévní endotel metabolismus patologie MeSH
- glykokalyx metabolismus patologie MeSH
- lidé MeSH
- zánět metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
