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81.
Izabela Fokt Slawomir Szymanski Stanislaw Skora Marcin Cybulski Timothy Madden Waldemar Priebe 《Carbohydrate research》2009,344(12):340
Modified d-glucose and d-mannose analogs are potentially clinically useful metabolic inhibitors. Biological evaluation of 2-deoxy-2-halo analogs has been impaired by limited availability and lack of efficient methods for their preparation. We have developed practical synthetic approaches to 2-deoxy-2-fluoro-, 2-chloro-2-deoxy-, 2-bromo-2-deoxy-, and 2-deoxy-2-iodo derivatives of d-glucose and d-mannose that exploit electrophilic addition reactions to a commercially available 3,4,6-tri-O-acetyl-d-glucal. 相似文献
82.
Among the structurally similar guanidinonaltrindole (GNTI) compounds, 5′-GNTI is an antagonist while 6′-GNTI is an agonist
of the κOR opioid receptor. To explore how a subtle alteration of the ligand structure influences the receptor activity, we
investigated two concurrent processes: the final steps of ligand binding at the receptor binding site and the initial steps
of receptor activation. To trace these early activation steps, the membranous part of the receptor was built on an inactive
receptor template while the extracellular loops were built using the ab initio CABS method. We used the simulated annealing
procedure for ligand docking and all-atom molecular dynamics simulations to determine the immediate changes in the structure
of the ligand–receptor complex. The binding of an agonist, in contrast to an antagonist, induced the breakage of the “3–7
lock” between helices TM3 and TM7. We also observed an action of the extended rotamer toggle switch which suggests that those
two switches are interdependent. 相似文献
83.
It is becoming increasingly apparent that G protein-coupled receptors (GPCRs) can exist and function as oligomers. This notion
differs from the classical view of signaling wherein the receptor has been presumed to be monomeric. Despite this shift in
views, the interpretation of data related to GPCR function is still largely carried out within the framework of a monomeric
receptor. Rhodopsin is a prototypical GPCR that initiates phototransduction. Like other GPCRs, the activity of rhodopsin is
regulated by phosphorylation and the binding of arrestin. In the current investigation, we have explored by modeling methods
the interaction of rhodopsin and arrestin under the assumption that either one or two rhodopsin molecules bind each arrestin
molecule. The dimeric receptor framework may provide a more accurate representation of the system and is therefore likely
to lead to a better and more accurate understanding of GPCR signaling. 相似文献
84.
G protein-coupled receptor (GPCR)-mediated signal transduction has been studied for more than a century. Despite the intense focus on this class of proteins, a molecular understanding of what constitutes the functional form of the receptor is still uncertain. GPCRs have traditionally been conceptualized as monomeric proteins, and this view has changed little over the years until relatively recently. Recent biochemical and biophysical studies have challenged this traditional concept, and point instead to a mechanistic view of signal transduction wherein the receptor functions as an oligomer. Cooperative interactions within such an oligomeric array may be critical for the propagation of an external signal across the cell membrane and to the G protein, and may therefore underlie the mechanistic basis of signaling. 相似文献
85.
A naturally occurring mutation of the opsin gene (T4R) in dogs affects glycosylation and stability of the G protein-coupled receptor 总被引:1,自引:0,他引:1
Zhu L Jang GF Jastrzebska B Filipek S Pearce-Kelling SE Aguirre GD Stenkamp RE Acland GM Palczewski K 《The Journal of biological chemistry》2004,279(51):53828-53839
Rho (rhodopsin; opsin plus 11-cis-retinal) is a prototypical G protein-coupled receptor responsible for the capture of a photon in retinal photoreceptor cells. A large number of mutations in the opsin gene associated with autosomal dominant retinitis pigmentosa have been identified. The naturally occurring T4R opsin mutation in the English mastiff dog leads to a progressive retinal degeneration that closely resembles human retinitis pigmentosa caused by the T4K mutation in the opsin gene. Using genetic approaches and biochemical assays, we explored the properties of the T4R mutant protein. Employing immunoaffinity-purified Rho from affected RHO(T4R/T4R) dog retina, we found that the mutation abolished glycosylation at Asn(2), whereas glycosylation at Asn(15) was unaffected, and the mutant opsin localized normally to the rod outer segments. Moreover, we found that T4R Rho(*) lost its chromophore faster as measured by the decay of meta-rhodopsin II and that it was less resistant to heat denaturation. Detergent-solubilized T4R opsin regenerated poorly and interacted abnormally with the G protein transducin (G(t)). Structurally, the mutation affected mainly the "plug" at the intradiscal (extracellular) side of Rho, which is possibly responsible for protecting the chromophore from the access of bulk water. The T4R mutation may represent a novel molecular mechanism of degeneration where the unliganded form of the mutant opsin exerts a detrimental effect by losing its structural integrity. 相似文献
86.
Schwarzenbacher R Canaves JM Brinen LS Dai X Deacon AM Elsliger MA Eshaghi S Floyd R Godzik A Grittini C Grzechnik SK Guda C Jaroszewski L Karlak C Klock HE Koesema E Kovarik JS Kreusch A Kuhn P Lesley SA McMullan D McPhillips TM Miller MA Miller MD Morse A Moy K Ouyang J Robb A Rodrigues K Selby TL Spraggon G Stevens RC van den Bedem H Velasquez J Vincent J Wang X West B Wolf G Hodgson KO Wooley J Wilson IA 《Proteins》2003,53(1):142-145
87.
Heine A Canaves JM von Delft F Brinen LS Dai X Deacon AM Elsliger MA Eshaghi S Floyd R Godzik A Grittini C Grzechnik SK Guda C Jaroszewski L Karlak C Klock HE Koesema E Kovarik JS Kreusch A Kuhn P Lesley SA McMullan D McPhillips TM Miller MA Miller MD Morse A Moy K Ouyang J Page R Robb A Rodrigues K Schwarzenbacher R Selby TL Spraggon G Stevens RC van den Bedem H Velasquez J Vincent J Wang X West B Wolf G Hodgson KO Wooley J Wilson IA 《Proteins》2004,56(2):387-391
88.
Schwarzenbacher R Jaroszewski L von Delft F Abdubek P Ambing E Biorac T Brinen LS Canaves JM Cambell J Chiu HJ Dai X Deacon AM DiDonato M Elsliger MA Eshagi S Floyd R Godzik A Grittini C Grzechnik SK Hampton E Karlak C Klock HE Koesema E Kovarik JS Kreusch A Kuhn P Lesley SA Levin I McMullan D McPhillips TM Miller MD Morse A Moy K Ouyang J Page R Quijano K Robb A Spraggon G Stevens RC van den Bedem H Velasquez J Vincent J Wang X West B Wolf G Xu Q Hodgson KO Wooley J Wilson IA 《Proteins》2004,55(3):768-771
89.
Spraggon G Schwarzenbacher R Kreusch A Lee CC Abdubek P Ambing E Biorac T Brinen LS Canaves JM Cambell J Chiu HJ Dai X Deacon AM DiDonato M Elsliger MA Eshagi S Floyd R Godzik A Grittini C Grzechnik SK Hampton E Jaroszewski L Karlak C Klock HE Koesema E Kovarik JS Kuhn P Levin I McMullan D McPhillips TM Miller MD Morse A Moy K Ouyang J Page R Quijano K Robb A Stevens RC van den Bedem H Velasquez J Vincent J von Delft F Wang X West B Wolf G Xu Q Hodgson KO Wooley J Lesley SA Wilson IA 《Proteins》2004,55(4):1078-1081
90.
Balcerzak M Hamade E Zhang L Pikula S Azzar G Radisson J Bandorowicz-Pikula J Buchet R 《Acta biochimica Polonica》2003,50(4):1019-1038
In this review the roles of specific proteins during the first step of mineralization and nucleation are discussed. Mineralization is initiated inside the extracellular organelles-matrix vesicles (MVs). MVs, containing relatively high concentrations of Ca2+ and inorganic phosphate (Pi), create an optimal environment to induce the formation of hydroxyapatite (HA). Special attention is given to two families of proteins present in MVs, annexins (AnxAs) and tissue-nonspecific alkaline phosphatases (TNAPs). Both families participate in the formation of HA crystals. AnxAs are Ca2+ - and lipid-binding proteins, which are involved in Ca2+ homeostasis in bone cells and in extracellular MVs. AnxAs form calcium ion channels within the membrane of MVs. Although the mechanisms of ion channel formation by AnxAs are not well understood, evidence is provided that acidic pH or GTP contribute to this process. Furthermore, low molecular mass ligands, as vitamin A derivatives, can modulate the activity of MVs by interacting with AnxAs and affecting their expression. AnxAs and other anionic proteins are also involved in the crystal nucleation. The second family of proteins, TNAPs, is associated with Pi homeostasis, and can hydrolyse a variety of phosphate compounds. ATP is released in the extracellular matrix, where it can be hydrolyzed by TNAPs, ATP hydrolases and nucleoside triphosphate (NTP) pyrophosphohydrolases. However, TNAP is probably not responsible for ATP-dependent Ca2+/phosphate complex formation. It can hydrolyse pyrophosphate (PPi), a known inhibitor of HA formation and a byproduct of NTP pyrophosphohydrolases. In this respect, antagonistic activities of TNAPs and NTP pyrophosphohydrolases can regulate the mineralization process. 相似文献