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Allosteric disulfide

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https://www.readbyqxmd.com/read/29222417/insulin-in-motion-the-a6-a11-disulfide-bond-allosterically-modulates-structural-transitions-required-for-insulin-activity
#1
Bianca van Lierop, Shee Chee Ong, Alessia Belgi, Carlie Delaine, Sofianos Andrikopoulos, Naomi L Haworth, John G Menting, Michael C Lawrence, Andrea J Robinson, Briony E Forbes
The structural transitions required for insulin to activate its receptor and initiate regulation of glucose homeostasis are only partly understood. Here, using ring-closing metathesis, we substitute the A6-A11 disulfide bond of insulin with a rigid, non-reducible dicarba linkage, yielding two distinct stereo-isomers (cis and trans). Remarkably, only the cis isomer displays full insulin potency, rapidly lowering blood glucose in mice (even under insulin-resistant conditions). It also posseses reduced mitogenic activity in vitro...
December 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29030429/activating-mutations-in-quorum-sensing-regulator-rgg2-and-its-conformational-flexibility-in-the-absence-of-an-intermolecular-disulfide-bond
#2
Reid V Wilkening, Glenn C Capodagli, Atul Khataokar, Kaitlyn M Tylor, Matthew B Neiditch, Michael J Federle
Rap/Rgg/NprR/PlcR/PrgX (RRNPP) quorum-sensing systems use extracellular peptide pheromones that are detected by cytoplasmic receptors to regulate gene expression in firmicute bacteria. Rgg-type receptors are allosterically regulated through direct pheromone binding to control transcriptional activity; however, the receptor activation mechanism remains poorly understood. Previous work has identified a disulfide bond between Cys-45 residues within the homodimer interface of Rgg2 from Streptococcus dysgalactiae (Rgg2Sd)...
October 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29023092/effect-of-the-flexible-regions-of-the-oncoprotein-mouse-double-minute-x-on-inhibitor-binding-affinity
#3
Lingyun Qin, Huili Liu, Rong Chen, Jingjing Zhou, Xiyao Cheng, Yao Chen, Yongqi Huang, Zhengding Su
The oncoprotein MdmX (mouse double minute X) is highly homologous to Mdm2 (mouse double minute 2) in terms of their amino acid sequences and three-dimensional conformations, but Mdm2 inhibitors exhibit very weak affinity for MdmX, providing an excellent model for exploring how protein conformation distinguishes and alters inhibitor binding. The intrinsic conformation flexibility of proteins plays pivotal roles in determining and predicting the binding properties and the design of inhibitors. Although the molecular dynamics simulation approach enables us to understand protein-ligand interactions, the mechanism underlying how a flexible binding pocket adapts an inhibitor has been less explored experimentally...
November 7, 2017: Biochemistry
https://www.readbyqxmd.com/read/28899696/serotonin-2a-receptor-disulfide-bridge-integrity-is-crucial-for-ligand-binding-to-different-signalling-states-but-not-for-its-homodimerization
#4
Alba Iglesias, Marta Cimadevila, Rocío Ailim de la Fuente, María Martí-Solano, María Isabel Cadavid, Marián Castro, Jana Selent, María Isabel Loza, José Brea
The serotonin 2A (5-HT2A) receptor is a G-protein coupled receptor (GPCR) with a conserved disulfide bridge formed by Cys(148) (transmembrane helix 3, TM3) and Cys(227) (extracellular loop 2, ECL-2). We hypothesized that disulfide bridges may determine serotonin 5-HT2A receptor functions such as receptor activation, functional selectivity and ligand recognition. We used the reducing agent dithiothreitol (DTT) to determine how the reduction of disulfide bridges affects radioligand binding, second messenger mobilization and receptor dimerization...
November 15, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28877869/hemoglobin-polymerization-via-disulfide-bond-formation-in-the-hypoxia-tolerant-turtle-trachemys-scripta-implications-for-antioxidant-defense-and-o2-transport
#5
Asbjørn Graver Petersen, Steen Vang Petersen, Sebastian Frische, Srdja Drakulic, Monika M Golas, Bjoern Sander, Angela Fago
The ability of many reptilian hemoglobins (Hbs) to form high-molecular weight polymers, albeit known for decades, has not been investigated in detail. Given that turtle Hbs often contain a high number of cysteine (Cys), potentially contributing to the red blood cell defense against reactive oxygen species, we have examined whether polymerization of Hb could occur via intermolecular disulfide bonds in red blood cells of freshwater turtle Trachemys scripta, a species that is highly tolerant of hypoxia and oxidative stress...
September 6, 2017: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/28825621/inhibitory-effect-of-bovine-lactoferrin-on-catechol-o-methyltransferase
#6
Masayuki Ikeda, Hiroshi Iijima, Ichizo Shinoda, Hiroshi Iwamoto, Yasuhiro Takeda
Lactoferrin (LF) is a well-known multifunctional protein. In this study, we report the inhibitory potency of bovine LF (bLF) on catechol-O-methyltransferase (COMT), which catalyzes methylation of catechol substrates. We found that bLF binds to and inhibits COMT using its N-terminal region. An N-terminal peptide fragment obtained from bLF by trypsin digestion showed a higher inhibitory activity than intact bLF. A synthetic fragment of the bLF N-terminal residues 6-50, with two pairs of disulfide bonds, also showed higher inhibitory activity than intact bLF...
August 19, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28770911/targeting-%C3%AE-cys93-in-hemoglobin-s-with-an-antisickling-agent-possessing-dual-allosteric-and-antioxidant-effects
#7
Tigist Kassa, M B Strader, Akito Nakagawa, Warren M Zapol, Abdu I Alayash
Sickle cell disease (SCD) is an inherited blood disorder caused by a β globin gene mutation of hemoglobin (HbS). The polymerization of deoxyHbS and its subsequent aggregation (into long fibers) is the primary molecular event which leads to red blood cell (RBC) sickling and ultimately hemolytic anemia. We have recently suggested that HbS oxidative toxicity may also contribute to SCD pathophysiology due to its defective pseudoperoxidase activity. As a consequence, a persistently higher oxidized ferryl heme is formed which irreversibly oxidizes "hotspot" residues (particularly βCys93) causing protein unfolding and subsequent heme loss...
September 20, 2017: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/28761055/a-single-channel-mechanism-for-pharmacological-potentiation-of-glun1-glun2a-nmda-receptors
#8
Divyan A Chopra, Kiran Sapkota, Mark W Irvine, Guangyu Fang, David E Jane, Daniel T Monaghan, Shashank M Dravid
NMDA receptors (NMDARs) contribute to several neuropathological processes. Novel positive allosteric modulators (PAMs) of NMDARs have recently been identified but their effects on NMDAR gating remain largely unknown. To this end, we tested the effect of a newly developed molecule UBP684 on GluN1/GluN2A receptors. We found that UBP684 potentiated the whole-cell currents observed under perforated-patch conditions and slowed receptor deactivation. At the single channel level, UBP684 produced a dramatic reduction in long shut times and a robust increase in mean open time...
July 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28623339/machine-learning-and-network-analysis-of-molecular-dynamics-trajectories-reveal-two-chains-of-red-ox-specific-residue-interactions-in-human%C3%A2-protein-disulfide-isomerase
#9
Razieh Karamzadeh, Mohammad Hossein Karimi-Jafari, Ali Sharifi-Zarchi, Hamidreza Chitsaz, Ghasem Hosseini Salekdeh, Ali Akbar Moosavi-Movahedi
The human protein disulfide isomerase (hPDI), is an essential four-domain multifunctional enzyme. As a result of disulfide shuffling in its terminal domains, hPDI exists in two oxidation states with different conformational preferences which are important for substrate binding and functional activities. Here, we address the redox-dependent conformational dynamics of hPDI through molecular dynamics (MD) simulations. Collective domain motions are identified by the principal component analysis of MD trajectories and redox-dependent opening-closing structure variations are highlighted on projected free energy landscapes...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28584050/allosteric-modulation-of-human-dopamine-transporter-activity-under-conditions-promoting-its-dimerization
#10
Mary Hongying Cheng, Jennie Garcia-Olivares, Steven Wasserman, Jennifer DiPietro, Ivet Bahar
The human dopamine (DA) transporter (hDAT) is a key regulator of neurotransmission and a target for antidepressants and addictive drugs. Despite the recent resolution of dDAT structures from Drosophila melanogaster, complete understanding of its mechanism of function and even information on its biological assembly is lacking. The resolved dDAT structures are monomeric, but growing evidence suggests that hDAT might function as a multimer, and its oligomerization may be relevant to addictive drug effects. Here, using structure-based computations, we examined the possible mechanisms of hDAT dimerization and its dynamics in a lipid bilayer...
July 28, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28450398/skeletal-overgrowth-causing-mutations-mimic-an-allosterically-activated-conformation-of-guanylyl-cyclase-b-that-is-inhibited-by-2-4-6-trinitrophenyl-atp
#11
COMPARATIVE STUDY
Deborah M Dickey, Neil M Otto, Lincoln R Potter
Activating mutations in the receptor for C-type natriuretic peptide (CNP), guanylyl cyclase B (GC-B, also known as Npr2 or NPR-B), increase cellular cGMP and cause skeletal overgrowth, but how these mutations affect GTP catalysis is poorly understood. The A488P and R655C mutations were compared with the known mutation V883M. Neither mutation affected GC-B concentrations. The A488P mutation decreased the EC50 5-fold, increased Vmax 2.6-fold, and decreased the Km 13-fold, whereas the R655C mutation decreased the EC50 5-fold, increased the Vmax 2...
June 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28432788/structure-of-fam20a-reveals-a-pseudokinase-featuring-a-unique-disulfide-pattern-and-inverted-atp-binding
#12
Jixin Cui, Qinyu Zhu, Hui Zhang, Michael A Cianfrocco, Andres E Leschziner, Jack E Dixon, Junyu Xiao
Mutations in FAM20A cause tooth enamel defects known as Amelogenesis Imperfecta (AI) and renal calcification. We previously showed that Fam20A is a secretory pathway pseudokinase and allosterically activates the physiological casein kinase Fam20C to phosphorylate secreted proteins important for biomineralization (Cui et al., 2015). Here we report the nucleotide-free and ATP-bound structures of Fam20A. Fam20A exhibits a distinct disulfide bond pattern mediated by a unique insertion region. Loss of this insertion due to abnormal mRNA splicing interferes with the structure and function of Fam20A, resulting in AI...
April 22, 2017: ELife
https://www.readbyqxmd.com/read/28393915/allosteric-inhibition-of-aminopeptidase-n-functions-related-to-tumor-growth-and-virus-infection
#13
César Santiago, Gaurav Mudgal, Juan Reguera, Rosario Recacha, Sébastien Albrecht, Luis Enjuanes, José M Casasnovas
Cell surface aminopeptidase N (APN) is a membrane-bound ectoenzyme that hydrolyzes proteins and peptides and regulates numerous cell functions. APN participates in tumor cell expansion and motility, and is a target for cancer therapies. Small drugs that bind to the APN active site inhibit catalysis and suppress tumor growth. APN is also a major cell entry receptor for coronavirus, which binds to a region distant from the active site. Three crystal structures that we determined of human and pig APN ectodomains defined the dynamic conformation of the protein...
April 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28302727/intersubunit-physical-couplings-fostered-by-the-left-flipper-domain-facilitate-channel-opening-of-p2x4-receptors
#14
Jin Wang, Liang-Fei Sun, Wen-Wen Cui, Wen-Shan Zhao, Xue-Fei Ma, Bin Li, Yan Liu, Yang Yang, You-Min Hu, Li-Dong Huang, Xiao-Yang Cheng, Lingyong Li, Xiang-Yang Lu, Yun Tian, Ye Yu
P2X receptors are ATP-gated trimeric channels with important roles in diverse pathophysiological functions. A detailed understanding of the mechanism underlying the gating process of these receptors is thus fundamentally important and may open new therapeutic avenues. The left flipper (LF) domain of the P2X receptors is a flexible loop structure, and its coordinated motions together with the dorsal fin (DF) domain are crucial for the channel gating of the P2X receptors. However, the mechanism underlying the crucial role of the LF domain in the channel gating remains obscure...
May 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28076818/one-way-allosteric-communication-between-the-two-disulfide-bonds-in-tissue-factor
#15
Beifei Zhou, Philip J Hogg, Frauke Gräter
Tissue factor (TF) is a transmembrane glycoprotein that plays distinct roles in the initiation of extrinsic coagulation cascade and thrombosis. TF contains two disulfide bonds, one each in the N-terminal and C-terminal extracellular domains. The C-domain disulfide, Cys186-Cys209, has a -RHStaple configuration in crystal structures, suggesting that this disulfide carries high pre-stress. The redox state of this disulfide has been proposed to regulate TF encryption/decryption. Ablating the N-domain Cys49-Cys57 disulfide bond was found to increase the redox potential of the Cys186-Cys209 bond, implying an allosteric communication between the domains...
January 10, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28003361/thioredoxin-1-selectively-activates-transglutaminase-2-in-the-extracellular-matrix-of-the-small-intestine-implications-for-celiac-disease
#16
Nicholas M Plugis, Brad A Palanski, Chih-Hisang Weng, Megan Albertelli, Chaitan Khosla
Transglutaminase 2 (TG2) catalyzes transamidation or deamidation of its substrates and is ordinarily maintained in a catalytically inactive state in the intestine and other organs. Aberrant TG2 activity is thought to play a role in celiac disease, suggesting that a better understanding of TG2 regulation could help to elucidate the mechanistic basis of this malady. Structural and biochemical analysis has led to the hypothesis that extracellular TG2 activation involves reduction of an allosteric disulfide bond by thioredoxin-1 (TRX), but cellular and in vivo evidence for this proposal is lacking...
February 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27899437/allosteric-control-of-antibody-prion-recognition-through-oxidation-of-a-disulfide-bond-between-the-ch-and-cl-chains
#17
Jun Zhao, Ruth Nussinov, Buyong Ma
Molecular details of the recognition of disordered antigens by their cognate antibodies have not been studied as extensively as folded protein antigens and much is still unknown. To follow the conformational changes in the antibody and cross-talk between its subunits and with antigens, we performed molecular dynamics (MD) simulations of the complex of Fab and prion-associated peptide in the apo and bound forms. We observed that the inter-chain disulfide bond in constant domains restrains the conformational changes of Fab, especially the loops in the CH1 domain, resulting in inhibition of the cross-talk between Fab subdomains that thereby may prevent prion peptide binding...
January 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/27853286/disulfide-mapping-the-voltage-sensing-mechanism-of-a-voltage-dependent-potassium-channel
#18
Tomohiro Nozaki, Shin-Ichiro Ozawa, Hitomi Harada, Tomomi Kimura, Masanori Osawa, Ichio Shimada
Voltage-dependent potassium (Kv) channels allow for the selective permeability of potassium ions in a membrane potential dependent manner, playing crucial roles in neurotransmission and muscle contraction. Kv channel is a tetramer, in which each subunit possesses a voltage-sensing domain (VSD) and a pore domain (PD). Although several lines of evidence indicated that membrane depolarization is sensed as the movement of helix S4 of the VSD, the detailed voltage-sensing mechanism remained elusive, due to the difficulty of structural analyses at resting potential...
November 17, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27774625/optimal-allosteric-stabilization-sites-using-contact-stabilization-analysis
#19
Alex Dickson, Christopher T Bailey, John Karanicolas
Proteins can be destabilized by a number of environmental factors such as temperature, pH, and mutation. The ability to subsequently restore function under these conditions by adding small molecule stabilizers, or by introducing disulfide bonds, would be a very powerful tool, but the physical principles that drive this stabilization are not well understood. The first problem lies is in choosing an appropriate binding site or disulfide bond location to best confer stability to the active site and restore function...
June 5, 2017: Journal of Computational Chemistry
https://www.readbyqxmd.com/read/27739308/critical-role-of-the-secondary-binding-pocket-in-modulating-the-enzymatic-activity-of-dusp5-toward-phosphorylated-erks
#20
Marat R Talipov, Jaladhi Nayak, Michael Lepley, Robert D Bongard, Daniel S Sem, Ramani Ramchandran, Rajendra Rathore
DUSP5 is an inducible nuclear dual-specificity phosphatase that specifically interacts with and deactivates extracellular signal-regulated kinases ERK1 and ERK2, which are responsible for cell proliferation, differentiation, and survival. The phosphatase domain (PD) of DUSP5 has unique structural features absent from other nuclear DUSPs, such as the presence of a secondary anion-binding site in the proximity of the reaction center and a glutamic acid E264 positioned next to the catalytic cysteine C263, as well as a remote intramolecular disulfide linkage...
November 8, 2016: Biochemistry
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