共查询到20条相似文献,搜索用时 31 毫秒
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Jianyun Lu Marcia I. Dawson Qiong Ying Hu Zebin Xia Jesse D. Dambacher Mao Ye Xiao‐Kun Zhang Ellen Li 《Magnetic resonance in chemistry : MRC》2009,47(12):1071-1080
The effect of retinoid X receptor (RXR) antagonists on the conformational exchange of the RXR ligand‐binding domain (LBD) remains poorly characterized. To address this question, we used nuclear magnetic resonance spectroscopy to compare the chemical shift perturbations induced by RXR antagonists and agonists on the RXRα LBD when partnered with itself as a homodimer and as the heterodimeric partner with the peroxisome proliferator‐activated receptor γ (PPARγ) LBD. Chemical shift mapping on the crystal structure showed that agonist binding abolished a line‐broadening effect caused by a conformational exchange on backbone amide signals for residues in helix H3 and other regions of either the homo‐ or hetero‐dimer, whereas binding of antagonists with similar binding affinities failed to do so. A lineshape analysis of a glucocorticoid receptor‐interacting protein 1 NR box 2 coactivator peptide showed that the antagonists enhanced peptide binding to the RXRα LBD homodimer, but to a lesser extent than that enhanced by the agonists. This was further supported by a lineshape analysis of the RXR C‐terminal residue, threonine 462 (T462) in the homodimer but not in the heterodimer. Contrary to the agonists, the antagonists failed to abolish a line‐broadening effect caused by a conformational exchange on the T462 signal corresponding to the RXRα LBD–antagonist–peptide ternary complex. These results suggest that the antagonists lack the ability of the agonists to shift the equilibrium of multiple RXRα LBD conformations in favor of a compact state, and that a PPARγ LBD‐agonist complex can prevent the antagonist from enhancing the RXRα LBD‐coactivator binding interaction. Copyright © 2009 John Wiley & Sons, Ltd. 相似文献
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Ito M Fukuzawa K Mochizuki Y Nakano T Tanaka S 《The journal of physical chemistry. A》2008,112(10):1986-1998
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《Angewandte Chemie (International ed. in English)》2017,56(20):5480-5484
Spiroketals are structural motifs found in many biologically active natural products, which has stimulated considerable efforts toward their synthesis and interest in their use as drug lead compounds. Despite this, the use of spiroketals, and especially bisbenzanulated spiroketals, in a structure‐based drug discovery setting has not been convincingly demonstrated. Herein, we report the rational design of a bisbenzannulated spiroketal that potently binds to the retinoid X receptor (RXR) thereby inducing partial co‐activator recruitment. We solved the crystal structure of the spiroketal–hRXRα–TIF2 ternary complex, and identified a canonical allosteric mechanism as a possible explanation for the partial agonist behavior of our spiroketal. Our co‐crystal structure, the first of a designed spiroketal–protein complex, suggests that spiroketals can be designed to selectively target other nuclear receptor subtypes. 相似文献
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Carlos H. T. P. Silva Andreia M. Leopoldino Eloiza H. T. Silva V. A. A. Espinoza C. A. Taft 《International journal of quantum chemistry》2005,102(6):1131-1135
The isotypes of RAR and RXR are retinoic acid and retinoid X acid receptors, respectively, whose ligand‐binding domain contains the ligand‐dependent activation function, with distinct pharmacological targets for retinoids, involved in the treatment of various cancers and skin diseases. Due to the major challenge which cancer treatment and cure still imposes after many decades to the international scientific community, there is actually considerable interest in new ligands with increased bioactivity. We have focused on the retinoid acid receptor, which is considered an interesting target for drug design. In this work, we carried out density functional geometry optimizations and different docking procedures. We performed screening in a large database (hundreds of thousands of molecules which we optimized at the AM1 level) yielding a set of potential bioactive ligands. A new ligand was selected and optimized at the B3LYP/6‐31G* level. A flexible docking program was used to investigate the interactions between the receptor and the new ligand. The result of this work is compared with several crystallographic ligands of RAR. Our theoretically more bioactive new ligand indicates stronger and more hydrogen bonds as well as hydrophobic interactions with the receptor. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005 相似文献
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Ito M Fukuzawa K Ishikawa T Mochizuki Y Nakano T Tanaka S 《The journal of physical chemistry. B》2008,112(38):12081-12094
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Dr. Paula Morales Dr. Gemma Navarro Marc Gómez-Autet Laura Redondo Prof. Dr. Javier Fernández-Ruiz Dr. Laura Pérez-Benito Dr. Arnau Cordomí Prof. Dr. Leonardo Pardo Prof. Dr. Rafael Franco Dr. Nadine Jagerovic 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(68):15839-15842
Single chemical entities with potential to simultaneously interact with two binding sites are emerging strategies in medicinal chemistry. We have designed, synthesized and functionally characterized the first bitopic ligands for the CB2 receptor. These compounds selectively target CB2 versus CB1 receptors. Their binding mode was studied by molecular dynamic simulations and site-directed mutagenesis. 相似文献
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Multiple Binding Sites Contribute to the Mechanism of Mixed Agonistic and Positive Allosteric Modulators of the Cannabinoid CB1 Receptor 下载免费PDF全文
Dr. Noureldin Saleh Dr. Oliver Hucke Gert Kramer Esther Schmidt Dr. Florian Montel Dr. Radoslaw Lipinski Prof. Dr. Boris Ferger Prof. Dr. Timothy Clark Prof. Dr. Peter W. Hildebrand Dr. Christofer S. Tautermann 《Angewandte Chemie (International ed. in English)》2018,57(10):2580-2585
The cannabinoid CB1 receptor (CB1R) is an abundant metabotropic G‐protein‐coupled receptor that has been difficult to address therapeutically because of CNS side effects exerted by orthosteric drug candidates. Recent efforts have focused on developing allosteric modulators that target CB1R. Compounds from the recently discovered class of mixed agonistic and positive allosteric modulators (Ago‐PAMs) based on 2‐phenylindoles have shown promising functional and binding properties as CB1R ligands. Here, we identify binding modes of both the CP 55,940 agonist and GAT228, a 2‐phenylindole allosteric modulator, by using our metadynamics simulation protocol, and quantify their affinity and cooperativity by atomistic simulations. We demonstrate the involvement of multiple adjunct binding sites in the Ago‐PAM characteristics of the 2‐phenylindole modulators and explain their ability to compete with orthosteric agonists at higher concentrations. We validate these results experimentally by showing the contribution of multiple sites on the allosteric binding of ZCZ011, another homologous member of the class, together with the orthosteric agonist. 相似文献
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Yuanyuan Lin Jing Xu Qianqian Jia Wei Sun Jia Fu Yanni Lv Shengli Han 《Journal of separation science》2020,43(13):2571-2578
Mas‐related G protein‐coupled receptor X2 was a mast cell–specific receptor mediating anaphylactoid reactions by activating mast cells degranulation, and it was also identified as a target for modulating mast cell–mediated anaphylactoid and inflammatory diseases. The anti‐anaphylactoid drugs used clinically disturb the partial effect of partial mediators released by mast cells. The small molecule of Mas‐related G protein‐coupled receptor X2 specific antagonists may provide therapeutic action for the anaphylactoid and inflammatory diseases in the early stage. In this study, the Mas‐related G protein‐coupled receptor X2 high expression cell membrane chromatography was coupled online with liquid chromatography and mass spectrometry and successfully used to screen anti‐anaphylactoid components from Magnolia biondii Pamp. Fargesin and pinoresinol dimethyl ether were identified as potential anti‐anaphylactoid components. Bioactivity of these two components were investigated by β hexosaminidase and histamine release assays on mast cells, and it was found that these two components could inhibit β hexosaminidase and histamine release in a concentration‐dependent manner. This Mas‐related G protein‐coupled receptor X2 high expression cell membrane chromatography coupled online with liquid chromatography and mass spectrometry system could be applied for screening potential anti‐anaphylactoid components from natural medicinal herbs. This study also provided a powerful system for drug discovery in natural medicinal herbs. 相似文献
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Qin Dai Carl Walkey Warren C. W. Chan 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2014,126(20):5193-5196
In protein‐rich environments such as the blood, the formation of a protein corona on receptor‐targeting nanoparticles prevents target recognition. As a result, the ability of targeted nanoparticles to selectively bind to diseased cells is drastically inhibited. Backfilling the surface of a targeted nanoparticle with polyethylene glycol (PEG) molecules is demonstrated to reduce the formation of the protein corona and re‐establishes specific binding. The length of the backfilled PEG molecules must be less than the length of the ligand linker; otherwise, PEG interferes with the binding of the targeting ligand to its corresponding cellular receptor. 相似文献
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Grimster NP Stump B Fotsing JR Weide T Talley TT Yamauchi JG Nemecz Á Kim C Ho KY Sharpless KB Taylor P Fokin VV 《Journal of the American Chemical Society》2012,134(15):6732-6740
Nicotinic acetylcholine receptors (nAChRs), which are responsible for mediating key physiological functions, are ubiquitous in the central and peripheral nervous systems. As members of the Cys loop ligand-gated ion channel family, neuronal nAChRs are pentameric, composed of various permutations of α (α2 to α10) and β (β2 to β4) subunits forming functional heteromeric or homomeric receptors. Diversity in nAChR subunit composition complicates the development of selective ligands for specific subtypes, since the five binding sites reside at the subunit interfaces. The acetylcholine binding protein (AChBP), a soluble extracellular domain homologue secreted by mollusks, serves as a general structural surrogate for the nAChRs. In this work, homomeric AChBPs from Lymnaea and Aplysia snails were used as in situ templates for the generation of novel and potent ligands that selectively bind to these proteins. The cycloaddition reaction between building-block azides and alkynes to form stable 1,2,3-triazoles was used to generate the leads. The extent of triazole formation on the AChBP template correlated with the affinity of the triazole product for the nicotinic ligand binding site. Instead of the in situ protein-templated azide-alkyne cycloaddition reaction occurring at a localized, sequestered enzyme active center as previously shown, we demonstrate that the in situ reaction can take place at the subunit interfaces of an oligomeric protein and can thus be used as a tool for identifying novel candidate nAChR ligands. The crystal structure of one of the in situ-formed triazole-AChBP complexes shows binding poses and molecular determinants of interactions predicted from structures of known agonists and antagonists. Hence, the click chemistry approach with an in situ template of a receptor provides a novel synthetic avenue for generating candidate agonists and antagonists for ligand-gated ion channels. 相似文献
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Application of plug–plug technique to ACE experiments for discovery of peptides binding to a larger target protein: A model study of calmodulin‐binding fragments selected from a digested mixture of reduced BSA 下载免费PDF全文
Kazuki Saito Mamiko Nakato Takaaki Mizuguchi Shinji Wada Hiromasa Uchimura Hiroshi Kataoka Shigeyuki Yokoyama Hiroshi Hirota Yoshiaki Kiso 《Electrophoresis》2014,35(6):846-854
To discover peptide ligands that bind to a target protein with a higher molecular mass, a concise screening methodology has been established, by applying a “plug–plug” technique to ACE experiments. Exploratory experiments using three mixed peptides, mastoparan‐X, β‐endorphin, and oxytocin, as candidates for calmodulin‐binding ligands, revealed that the technique not only reduces the consumption of the protein sample, but also increases the flexibility of the experimental conditions, by allowing the use of MS detection in the ACE experiments. With the plug–plug technique, the ACE–MS screening methodology successfully selected calmodulin‐binding peptides from a random library with diverse constituents, such as protease digests of BSA. Three peptides with Kd values between 8–147 μM for calmodulin were obtained from a Glu‐C endoprotease digest of reduced BSA, although the digest showed more than 70 peaks in its ACE–MS electropherogram. The method established here will be quite useful for the screening of peptide ligands, which have only low affinities due to their flexible chain structures but could potentially provide primary information for designing inhibitors against the target protein. 相似文献
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Prof. Dr. Klaus Mohr Dr. Jens Schmitz Ramona Schrage Priv.‐Doz. Christian Tränkle Prof. Dr. Ulrike Holzgrabe 《Angewandte Chemie (International ed. in English)》2013,52(2):508-516
Cell‐membrane‐spanning G protein coupled receptors (GPCRs) belong to the most important therapeutic target structures. Endogenous transmitters bind from the outer side of the membrane to the “orthosteric” binding site either deep in the binding pocket or at the extracellular N‐terminal end of the receptor protein. Exogenous modulators that utilize a different, “allosteric”, binding site unveil a pathway to receptor subtype‐selectivity. However, receptor activation through the orthosteric area is often more powerful. Recently there has been evidence that orthosteric/allosteric, in other words “dualsteric”, hybrid compounds unite subtype selectivity and receptor activation. These “bitopic” modulators channelreceptor activation and subsequent intracellular signaling into a subset of possible routes. This concept offers access to GPCR modulators with an unprecedented receptor‐subtype and signaling selectivity profile and, as a consequence, to drugs with fewer side effects. 相似文献
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Hadley A. Iliff Diane L. Lynch Evangelia Kotsikorou Patricia H. Reggio 《Journal of computational chemistry》2011,32(10):2119-2126
The cannabinoid CB1 receptor is a class A G protein‐coupled receptor (GPCR) that is the most widely expressed GPCR in the brain. Many GPCRs contain allosteric binding sites for endogenous and/or synthetic ligands, which are topographically distinct from the agonist‐binding site that is known as the orthosteric site. While both endogenous and synthetic ligands that act at the CB1 orthosteric site have been known for some time, compounds that act at a CB1 allosteric site have only recently been discovered. The most studied of these is 5‐chloro‐3‐ethyl‐1H‐indole‐2‐carboxylic acid [2‐(4‐piperidin‐1‐ylphenyl)ethyl]amide (Org27569). Because allosteric ligands are thought to act through conformational changes in the receptor that are transmitted from the allosteric to the orthosteric site, computational studies of the structural and dynamic interactions of Org27569 with the CB1 receptor are crucial to achieve a molecular level understanding of the basis of action of this important new class of compounds. To date, such computational studies have not been possible due to the lack of a complete set of molecular mechanics force field parameters for Org27569. Here, we present the development of missing CHARMM force field parameters for Org27569 using previously published methods and the validation and application of these new parameters using normal mode analysis and molecular dynamics simulations combined with experimental infrared measurements. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011 相似文献
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A Combination of Spin Diffusion Methods for the Determination of Protein–Ligand Complex Structural Ensembles 下载免费PDF全文
Dr. Jens Pilger Dr. Adam Mazur Dr. Peter Monecke Dr. Herman Schreuder Dr. Bettina Elshorst Dr. Stefan Bartoschek Dr. Thomas Langer Dr. Alexander Schiffer Dr. Isabelle Krimm Melanie Wegstroth Dr. Donghan Lee Dr. Gerhard Hessler Dr. K.‐Ulrich Wendt Dr. Stefan Becker Prof. Dr. Christian Griesinger 《Angewandte Chemie (International ed. in English)》2015,54(22):6511-6515
Structure‐based drug design (SBDD) is a powerful and widely used approach to optimize affinity of drug candidates. With the recently introduced INPHARMA method, the binding mode of small molecules to their protein target can be characterized even if no spectroscopic information about the protein is known. Here, we show that the combination of the spin‐diffusion‐based NMR methods INPHARMA, trNOE, and STD results in an accurate scoring function for docking modes and therefore determination of protein–ligand complex structures. Applications are shown on the model system protein kinase A and the drug targets glycogen phosphorylase and soluble epoxide hydrolase (sEH). Multiplexing of several ligands improves the reliability of the scoring function further. The new score allows in the case of sEH detecting two binding modes of the ligand in its binding site, which was corroborated by X‐ray analysis. 相似文献