碘的生物无机化学研究进展—碘对甲状腺激素生物活性的结构作用探讨

本文综述甲状腺激素相关研究的进展 ,探讨碘在甲状腺激素与细胞内激素受体蛋白结合中的结构作用。文中评述了关于甲状腺激素与血浆运载蛋白和细胞内受体蛋白结合的溶液亲合性、结构研究和甲状腺激素碘代酚环的分子识别特性与碘的结构效应模拟研究的数据结果 ,并就碘对激素 受体蛋白结合的结构作用提出了作者的观点     

3,5-二甲基-D,L-酪氨酸与铜(Ⅱ)和芳香氮碱配体形成混配配合物的稳定性研究

碘是脊椎动物生命过程中重要的必需元素之一,被动物体吸收后主要用于甲状腺激素的生物合成.甲状腺激素与血浆中运载蛋白和细胞内受体蛋白结合的溶液亲和性及结构研究表明,碘具有结构作用[1].     

预防甲状腺肿的碘

成年人体内约含碘 1 0～ 3 0毫克 ,约为体重的三百万分之一 ,而其中 70 %～ 80 %的碘集中在靠近喉头的甲状腺中。碘是构成甲状腺激素的核心成员 ,碘对人体的功用也是通过甲状腺激素来实现的。甲状腺是人体的重要器官 ,它好似一个碘的捕捉器 ,它把进入体内的碘追捕、集中起来 ,然后合成甲状腺素。估计成年人每天合成的甲状腺素约为 1 0 0微克。合成的甲状腺素立即进入血液 ,并被转运至全身各组织 ,在各组织中发挥它的重要作用。甲状腺激素的作用是多样的。它能刺激碳水化合物、蛋白质、脂肪和无机盐的代谢 ;促进蛋白质的合成和机体的生长发育…     

细胞表面的智能传感器:G蛋白偶联受体——2012年诺贝尔化学奖解读

美国科学家Robert J.Lefkowitz(罗伯特.莱夫科维茨)和Brian K.Kobilka(布莱恩.克比尔卡)因为突破性地揭示了G蛋白偶联受体(G-protein-coupled receptors,GPCRs)这一重要受体蛋白家族的内在工作机制而获得2012年诺贝尔化学奖。G蛋白偶联受体可以与激素和G蛋白结合形成三重复合物结构,从而活化G蛋白,引发生理反应。G蛋白偶联受体的结构及工作机制的发现与研究具有重要的理论价值和医药应用价值。     

分光光度法测定食盐中碘的含量

碘是甲状腺合成甲状腺激素的主要成分,这种激素能促进人体的新陈代谢和生长发育。人体缺碘易患缺碘性疾病,如地方性甲状腺肿、地方性克汀病等,我国是碘缺乏病流行严重的国家,目前主要是在食盐中加入碘(以碘酸钾形式加入)并且严格控制碘的加入量,为此,测定食盐中碘含量非常重要。食盐中含碘量的测定常用的方法有滴定分析法[1]和萃取光度法[2]等,利用碘酸钾作氧化剂的氧化褪色光度法有较多的研究[3-4],而氧化显色光度法研究得较     

化学发光酶免疫法测定游离三碘甲腺原氨酸

以辣根过氧化物酶为三碘甲腺原氨酸类似物的标记物,鲁米诺为化学发光反应底物,建立了一种高灵敏度化学发光免疫检测游离三碘甲腺原氨酸的方法。该法线性范围为0.90~80 ng/L,批内变异小于12.1%,批间相对标准偏差均小于15%,其余各项指标均良好。利用本法对血清样品进行了测定,关于甲状腺机能亢进组病人的临床诊断符合率达到83.3%。与其它化学发光免疫分析方法比较所得相关系数为0.9005。在方法条件选择上,以尽可能保持游离激素和蛋白结合激素之间的平衡为原则,提高游离三碘甲腺原氨酸浓度测定的准确性。     

高选择性比色识别碘离子的氨基硫脲类阴离子受体

设计合成了一系列基于氨基硫脲的阴离子受体（M1～M4）.此类受体以氨基硫脲基团为识别位点,以硝基苯基为信号报告基团,其中受体M1和M3可在乙腈溶液中高选择性的比色识别碘离子.在受体M1或M3的乙腈溶液中加入I^–时,溶液的颜色由浅红色变成无色,而加入其他离子如F^–,Cl^–,Br^–,AcO^–,HSO4^–,H2PO4^–,ClO4^–等阴离子时,受体溶液不会褪色.通过紫外滴定和核磁滴定等方法研究了受体选择性比色识别碘离子的机理.结果表明,受体通过其氨基硫脲基团上的三个NH质子与碘离子形成的三重氢键选择性的结合碘离子.在此过程中,受体构型发生转变,从而导致了颜色变化,产生了比色识别的效果.此类阴离子受体具有合成方法简便,产率高,识别效果好等优点.     

信息

微量元素与激素微量元素可以在激素的分泌、活性以及与组织的结合等各个环节上影响激素。例如,锌与生长激素相结合,可使之更稳定,不易失活。体内锌态势的改变可影响胰岛素的合成、分泌、贮藏和活力,锌与胰岛素蛋白质结合形成一种复合物,可延长胰岛素的作用时间,锌与性激素的关系也十分密切。锌促进睾丸酮的合成分泌。锌可能控制激素与受体的结合过程。微量元素碘是合成甲状腺素的关键成分。甲状腺素包括T4和T3。T4的活性很低。T4经含硒酶催化而脱碘,转变为T3。T3的活性比T4高几倍。所以缺硒可以加重缺碘所造成的危害。(颜世铭)人体微量元…     

α2A肾上腺素受体的同源模建及与Yohimbine的对接研究

通过对比多个与α2A-肾上腺素受体同属G-蛋白偶联受体的视紫红质蛋白序列,选择以相似性最大的牛视紫红质蛋白为模板,同源模建了α2A-肾上腺素受体的跨膜结构,并在结构中找到了体积为0.090 nm3,已被报导的活性残基包围的活性位点.运用分子力学与动力学方法研究了此结构突变前后与抑制剂Yohimbine的对接情况,得到了与文献报道相吻合的结果.同时对接研究结果发现,在α2A-肾上腺素受体的结合位点周围的一个由色氨酸和两个苯丙氨酸组成的局部疏水区对抑制剂有稳定作用,并且天冬氨酸113作为氢键受体也对稳定抑制剂有重要作用.     

基于金纳米簇检测碘单质的荧光分析方法研究

以蛋白质保护的金纳米簇Au NCs@BSA作为荧光探针,高灵敏地检测碘含量。结果表明,碘单质可引起金纳米簇的荧光猝灭,在2.0 nmol/L~35μmol/L浓度范围内具有良好的线性响应关系,检出限为1.8nmol/L。利用建立的方法对水样中的碘单质进行定量测定,并与ICP-MS检测结果进行对比,结果证明该方法在实际样品的检测中具有应用潜力。同时基于Au NCs@BSA与碘浓度的依赖效应,改变温度,诱导荧光响应变化,利用热力学计算,深入探讨了Au NCs@BSA与碘单质之间的作用机理,圆二色谱与红外光谱的结果表明碘单质引起的配体BSA的蛋白二级结构变化,诱导了Au NCs@BSA的荧光猝灭。该文的机理研究为无机小分子与蛋白质保护的金纳米簇之间的相互作用提供了参考。     

Models for the binding of amiodarone to the thyroid hormone receptor

Summary The antiarrhythmic drug amiodarone has recently been characterized as the first known thyroid hormone antagonist. Its mode of interaction with the thyroid hormone receptor is therefore of interest. A computational analysis of the conformational flexibility of amiodarone using molecular mechanics and the semiempirical molecular orbital method AM1 has been performed. The molecular mechanics studies show that the low-energy conformations of the benzoylbenzofuran portion of amiodarone can be grouped into 4 distinct classes, while the diethylaminoethoxy side chain is extremely flexible. Conformers representative of the 4 low-energy classes were fitted to an extended thyroid hormone receptor model. Four independent modes in which amiodarone could bind to the thyroid hormone receptor site were evaluated.     

Ab initio modelling of the N-terminal domain of the secretin receptors

G protein coupled receptors of the secretin family are activated by peptide hormones of about 30 residues in length. There is considerable sequence homology within both the hormone and receptor families. The receptors possess in addition to the integral membrane domain a characteristic extracellular domain of about 120 residues in length, having conserved cysteine residues, which are involved in disulphide bridge formation, and tryptophanes, which have been shown to be critical for hormone binding. This extracellular domain does not have detectable homology to any known protein fold. In order to be able to propose a structure for this domain we have used ab initio prediction methods combined with constraints based on experimental results for the disulphide connectivity. The results of computational tools for predicting secondary structure and accessibility, together with ligand binding and mutational data and other structural considerations were used in the ab initio protein folding programs DRAGON and GADGET and also the simpler program RAMBLE, which was able to explore different permutations of disulphide bond connectivity, tryptophan side chain orientation and chain topology. The methods generated a limited number of plausible models but no single unique solution was found under the constraints. One of these was refined into a full atomic model that contained a possible peptide binding site comprising the most conserved residues.     

Evaluation of absorbed dose in thyroid follicles due to short-lived iodines irradiation using the Monte Carlo method

Summary Thyroid cells are arranged in spheres called follicles of different sizes, in which most of the iodine in the body concentrates. For dose assessment in follicles, it is necessary to consider specific emissions of iodine isotopes in the calculation. Hence, the aim of this work was to evaluate the contribution of ¹³¹I and short-lived iodines to the absorbed dose in thyroid cells. Thus, the interaction of emissions from isotopes with follicles was carried out using the MCNP4C code. The results showed that the contribution of short-lived iodines for absorbed dose per disintegration is about 70%.     

Isoleucine Residues Determine Chiral Discrimination of Odorant-Binding Protein

Enzymes, receptors, and carrier proteins discriminate between enantiomers of natural and synthetic chemicals. Whereas the structural details of this phenomenon have been investigated in enzymes and receptors, much less is known for carrier proteins of hydrophobic ligands, particularly concerning the contribution of asymmetric centers in the side chains of amino acids to chirally selective binding. Working with a pig odorant-binding protein, we have found that the replacement of either one or both isoleucine residues in the binding pocket by leucines abolishes discrimination of menthol and carvone enantiomers. The results indicate that isoleucines are crucial for chiral discrimination of hydrophobic ligands, and that asymmetry in the side chain may be as important as the overall asymmetry of the protein. The results provide suggestions and guidelines for improving chiral selectivity of binding proteins and enzymes, with consequent applications in the production of enantiomerically pure drugs.     

A carrier protein strategy yields the structure of dalbavancin

Many large natural product antibiotics act by specifically binding and sequestering target molecules found on bacterial cells. We have developed a new strategy to expedite the structural analysis of such antibiotic-target complexes, in which we covalently link the target molecules to carrier proteins, and then crystallize the entire carrier-target-antibiotic complex. Using native chemical ligation, we have linked the Lys-D-Ala-D-Ala binding epitope for glycopeptide antibiotics to three different carrier proteins. We show that recognition of this peptide by multiple antibiotics is not compromised by the presence of the carrier protein partner, and use this approach to determine the first-ever crystal structure for the new therapeutic dalbavancin. We also report the first crystal structure of an asymmetric ristocetin antibiotic dimer, as well as the structure of vancomycin bound to a carrier-target fusion. The dalbavancin structure reveals an antibiotic molecule that has closed around its binding partner; it also suggests mechanisms by which the drug can enhance its half-life by binding to serum proteins, and be targeted to bacterial membranes. Notably, the carrier protein approach is not limited to peptide ligands such as Lys-D-Ala-D-Ala, but is applicable to a diverse range of targets. This strategy is likely to yield structural insights that accelerate new therapeutic development.     

Who Binds Better? Let Alphafold2 Decide!

Deep learning is revolutionizing structural biology to an unprecedented extent. Spearheaded by DeepMind's Alphafold2, structural models of high quality can be generated, and are now available for most known proteins and many protein interactions. The next challenge will be to leverage this rich structural corpus to learn about binding: which protein can contact which partner(s), and at what affinity? In a recent study, Chang and Perez have presented an elegant approach towards this challenging goal for interactions that involve a short peptide binding to its receptor. The basic idea is straightforward: given a receptor that binds to two peptides, if the receptor sequence is presented with both peptides together at the same time, AlphaFold2 should model the tighter binding peptide into the binding site, while excluding the second. A simple idea that works!     

Hammett analysis of selective thyroid hormone receptor modulators reveals structural and electronic requirements for hormone antagonists

Selective thyroid hormone modulators that function as isoform-selective agonists or antagonists of the thyroid hormone receptors (TRs) might be therapeutically useful in diseases associated with aberrant hormone signaling. The most potent thyroid hormone antagonist reported to date is NH-3. To explore the significance of the 5'-p-nitroaryl moiety of NH-3 and understand what chemical features are important to confer antagonism, we sought to expand the structure-activity relationship data for the class of 5'-phenylethynyl GC-1 derivatives. Herein, we describe an improved synthetic route utilizing palladium-catalyzed chemistry for efficient access to a series of 5'-phenylethynyl compounds with varying size and electronic properties. We prepared and tested sixteen analogues for TR binding and transactivation activity. Substitution at the 5'-position decreased binding affinity, but retained TRbeta-selectivity. In transactivation assays, the analogues displayed a spectrum of agonist, antagonist, and mixed agonist/antagonist activity that correlated with electronic character in a Hammett analysis between sigma substituent value and TR modulation. Analogues NH-5, NH-7, NH-9, NH-11, and NH-23 displayed full antagonist activity with reduced potency compared to NH-3, indicating the nitro group is not required for antagonism. However, para-substitution with strong electron withdrawing properties on the 5'-aryl extension is important for antagonist activity, and antagonist potency-but not ligand receptor binding-was found to correlate linearly with the sigma values for the electron withdrawing substituents.