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31.
Ah-lim Tsai Eva Strobel-Jager Kenneth K. Wu 《Journal of computer-aided molecular design》1991,5(2):135-148
Summary To elucidate the conformation of receptor-associated prostacyclin (PGI2), we first performed structure-activity correlation analysis of over 200 PGI2 analogues and derived from this analysis several crucial features pertaining to structural requirements for PGI2 activity [Ah-lim Tsai and Kenneth K. Wu, Eicosanoids, 2 (1989) 131–143]. These structural features proved to be useful guidelines for selecting model molecules for further investigations by molecular mechanics. By properly selecting four analogues with either rigid or uniquely oriented -side chain structure for geometric fitting, we succeeded in maximally minimizing the degree of freedom of the carboxylate terminus of PGI2. We were able to define the spatial relationship among the four critical functional groups, i.e., C1-COOH, C6a-O, C11-OH and C15-OH. More information is needed, however, to define the geometry of the -side chain, particularly for the moiety beyond C15. Nevertheless, results from structure-activity correlation analysis and molecular modeling provide useful information regarding the conformation of receptor-associated PGI2, which assumes an elongated conformation instead of the traditional hairpin structure. 相似文献
32.
Thawatchai Tuntulani Praput Thavornyutikarn Sirilux Poompradub Nongnuj Jaiboon Vithaya Ruangpornvisuti Narongsak Chaichit Zouhair Asfari Jacques Vicens 《Tetrahedron》2002,58(52):10277-10285
Tripodal aza crown ether calix[4]arenes, 5a, 5b, 6a and 6b, have been synthesized. The structure of protonated 5a was elucidated by X-ray crystallography to be a self-threaded rotaxane. Complexation studies of 5a and 5b towards anions using Na+ as countercation were carried out by 1H NMR titration in dimethylsulfoxide-d6 and the mixture of chloroform-d and methanol-d4, respectively. Ligands 5a and 5b were able to form 1:1 complexes with Br−, I− and NO3− and the complexation stability varied as follows: NO3−>I−>Br−. The effect of countercation on anion complexation was also investigated. The results showed that the association constants of 5a towards Br− in the presence of various cations varied as K+>Bu4N+>Na+. The enhancement in anion complexation ability of 5a may result from the rearrangement of the tripodal ammonium unit in the presence of K+. The neutral forms, 6a and 6b, were able to form complexes with transition metal ions such as Co2+, Ni2+, Cu2+ and Zn2+. The stability of the complexes followed the sequence: Ni2+2+Cu2+Zn2+. Compounds 6a and 6b may, therefore, potentially be used as either transition metal ion or anion receptors that can be controlled by pH of the solution. 相似文献
33.
Yuri Hirayama Naohiko Anzai Hiroyuki Kinouchi Schuichi Koizumi 《Molecules (Basel, Switzerland)》2022,27(12)
A sub-lethal ischemic episode (preconditioning [PC]) protects neurons against a subsequent lethal ischemic injury. This phenomenon is known as ischemic tolerance. PC itself does not cause brain damage, but affects glial responses, especially astrocytes, and transforms them into an ischemia-resistant phenotype. P2X7 receptors (P2X7Rs) in astrocytes play essential roles in PC. Although P2X7Rs trigger inflammatory and toxic responses, PC-induced P2X7Rs in astrocytes function as a switch to protect the brain against ischemia. In this review, we focus on P2X7Rs and summarize recent developments on how astrocytes control P2X7Rs and what molecular mechanisms they use to induce ischemic tolerance. 相似文献
34.
Chenlin Feng Xuesong Wang Willem Jespers Rongfang Liu Sofía Denise Zamarbide Losada Marina Gorostiola Gonzlez Gerard J. P. van Westen Erik H. J. Danen Laura H. Heitman 《Molecules (Basel, Switzerland)》2022,27(15)
The adenosine A2A receptor (A2AAR) is a class A G-protein-coupled receptor (GPCR). It is an immune checkpoint in the tumor micro-environment and has become an emerging target for cancer treatment. In this study, we aimed to explore the effects of cancer-patient-derived A2AAR mutations on ligand binding and receptor functions. The wild-type A2AAR and 15 mutants identified by Genomic Data Commons (GDC) in human cancers were expressed in HEK293T cells. Firstly, we found that the binding affinity for agonist NECA was decreased in six mutants but increased for the V275A mutant. Mutations A165V and A265V decreased the binding affinity for antagonist ZM241385. Secondly, we found that the potency of NECA (EC50) in an impedance-based cell-morphology assay was mostly correlated with the binding affinity for the different mutants. Moreover, S132L and H278N were found to shift the A2AAR towards the inactive state. Importantly, we found that ZM241385 could not inhibit the activation of V275A and P285L stimulated by NECA. Taken together, the cancer-associated mutations of A2AAR modulated ligand binding and receptor functions. This study provides fundamental insights into the structure–activity relationship of the A2AAR and provides insights for A2AAR-related personalized treatment in cancer. 相似文献
35.
Longlong Ren Zhenxiang Jing Fei Xia John Zenghui Zhang Yang Li 《Molecules (Basel, Switzerland)》2022,27(14)
Numerous experiments have revealed that fullerene (C60) and its derivatives can bind to proteins and affect their biological functions. In this study, we explored the interaction between fullerine and the β2-adrenergic receptor (β2AR). The MD simulation results show that fullerene binds with the extracellular loop 2 (ECL2) and intracellular loop 2 (ICL2) of β2AR through hydrophobic interactions and π–π stacking interactions. In the C60_in1 trajectory, due to the π–π stacking interactions of fullerene molecules with PHE and PRO residues on ICL2, ICL2 completely flipped towards the fullerene direction and the fullerene moved slowly into the lipid membrane. When five fullerene molecules were placed on the extracellular side, they preferred to stack into a stable fullerene cluster (a deformed tetrahedral aggregate), and had almost no effect on the structure of β2AR. The hydroxyl groups of fullerene derivatives (C60(OH)X, X represents the number of hydroxyl groups, X = 4, 8) can form strong hydrogen bonds with the ECL2, helix6, and helix7 of β2AR. The hydroxyl groups firmly grasp the β2AR receptor like several claws, blocking the binding entry of ligands. The simulation results show that fullerene and fullerene derivatives may have a significant effect on the local structure of β2AR, especially the distortion of helix4, but bring about no great changes within the overall structure. It was found that C60 did not compete with ligands for binding sites, but blocked the ligands’ entry into the pocket channel. All the above observations suggest that fullerene and its derivatives exhibit certain cytotoxicity. 相似文献
36.
Shaymaa Khazaal Julien Harb Mohamad Rima Cdric Annweiler Yingliang Wu Zhijian Cao Ziad Abi Khattar Christian Legros Herv Kovacic Ziad Fajloun Jean-Marc Sabatier 《Molecules (Basel, Switzerland)》2022,27(9)
COVID-19 has expanded across the world since its discovery in Wuhan (China) and has had a significant impact on people’s lives and health. Long COVID is a term coined by the World Health Organization (WHO) to describe a variety of persistent symptoms after acute SARS-CoV-2 infection. Long COVID has been demonstrated to affect various SARS-CoV-2-infected persons, independently of the acute disease severity. The symptoms of long COVID, like acute COVID-19, consist in the set of damage to various organs and systems such as the respiratory, cardiovascular, neurological, endocrine, urinary, and immune systems. Fatigue, dyspnea, cardiac abnormalities, cognitive and attention impairments, sleep disturbances, post-traumatic stress disorder, muscle pain, concentration problems, and headache were all reported as symptoms of long COVID. At the molecular level, the renin-angiotensin system (RAS) is heavily involved in the pathogenesis of this illness, much as it is in the acute phase of the viral infection. In this review, we summarize the impact of long COVID on several organs and tissues, with a special focus on the significance of the RAS in the disease pathogenesis. Long COVID risk factors and potential therapy approaches are also explored. 相似文献
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39.
We present a rather generic model for toxin (ricin) inhibition of protein biosynthesis in eukaryotic cells. We also study reduction of the ricin toxic effects with application of antibodies against the RTB subunit of ricin molecules. Both species initially are delivered extracellularly. The model accounts for the pinocytotic and receptor-mediated toxin endocytosis and the intact toxin exocytotic removal out of the cell. The model also includes the lysosomal toxin destruction, the intact toxin motion to the endoplasmic reticulum (ER) for separation of its molecules into the RTA and RTB subunits, and the RTA chain translocation into the cytosol. In the cytosol, one portion of the RTA undergoes degradation via the ERAD. The other its portion can inactivate ribosomes at a large rate. The model is based on a system of deterministic ODEs. The influence of the kinetic parameters on the protein concentration and antibody protection factor is studied in detail. 相似文献
40.
Dr. Sumith A. Kularatne Vishal Deshmukh Dr. Marco Gymnopoulos Dr. Sandra L. Biroc Dr. Jinming Xia Shailaja Srinagesh Dr. Ying Sun Dr. Ning Zou Dr. Mark Shimazu Dr. Jason Pinkstaff Dr. Semsi Ensari Nick Knudsen Anthony Manibusan Dr. Jun Y. Axup Dr. Chan Hyuk Kim Prof. Vaughn V. Smider Dr. Tsotne Javahishvili Prof.Dr. Peter G. Schultz 《Angewandte Chemie (International ed. in English)》2013,52(46):12101-12104