Exendin-4中13号残基的分子动力学模拟

Exendin-4作为胰腺GLP-1受体上的一种有效的激活剂, 是一种含有39个氨基酸残基的多肽, 其第13号氨基酸Gln突变为Tyr, 使活性增强. 应用分子动力学模拟方法, 分别优化了突变前后, Exendin-4与蛋白的复合物结构, 并对整体结构的性质、静电势、相互作用模式及能量进行了分析. 阐明了Gln突变为Tyr的活性增强的内在原因, 结果表明, 突变的Exendin-4能够通过改变自身结构的局部柔性调整与蛋白受体相互作用, 从而可以改善Exendin-4与其蛋白受体的结合能力.     

Exendin-4类似物的生物活性及结构

针对Exendin-4的N端螺旋中第10~18位氨基酸序列LSKQMEEEA设计了Ex1, Ex2序列, 并进行活性、稳定性及其结构方面的研究, 为进一步设计具有Exendin-4活性的短肽抗酶解序列提供了理论依据, 进而为开发可供口服的类肽糖尿病药物奠定了结构理论基础.     

SDS胶束溶液中Exendin-4活性类似物的结构分析

Exendin-4（EX-4）是一种治疗II型糖尿病的潜在药物。研究发现用β-Asp和Gln同时替换EX-4中的Glu3和Tyr13得到的EX-4类似物比EX-4有更好的降糖效果和抗水解的稳定性。本文用核磁共振方法研究了SDS胶束溶液中EX-4和这种活性类似物的三维空间结构。结果表明在SDS胶束溶液中EX-4活性类似物与EX-4原始肽的结构都由具有α螺旋卷曲构象的中间区域和灵活的N端区域及形成Trp-cage结构的C端区域构成,但与原始肽结构不同的是类似物的螺旋区域向N端扩展了3个残基,螺旋结构向N端的延长可能改善了底物与受体的亲和力,提高了生物活性。     

C_4O_4~(m-)(m=0,1,2,3,4)的从头算研究——1.平衡几何和相对稳定性

在RHF(基离子在UHF和ROHF)/6-31G,6-31G~*和6-31 G水平优化得到C_4O_4~(m-)(m=0,1,2,3,4)的平衡几何构型,发现从中性分子(C_4O_4)到负4价离子(C_4O_4~(4-))经历了一个由非芳香性到芳香性再到反芳香性的结构变化过程,它们的相对稳定性为C_4O_4~->C_4O_4~(2-)>C_4O_4>C_4O_4~(3-)>C_4O_4~(4-).     

单个离子标准迁移自由能的测定

本文采用活化分析法测定参考解质Ph4AsPh4B晶体在水和有机溶剂中的溶解度和计算了它从水迁移到有机溶剂中的标准迁移Gibbs自由能△^s^wG^0t.根据Ph4AsPh4B假定,求得参考正负离子Ph4As^+和Ph4B^-的标准迁移Gibbs自由能.又通过测定Ph4AsTcO4,CsPh4B,KPh4B和CsTCO4等晶体在水和有机溶剂站的溶解度,求得TcO4^-,K^+,Cs^+等离子的标准迁移自由能,并对结果进行了讨论.     

四角锥形结构化合物BeB4X4(X=H，F，Cl)，HBB4H4与BB4H4+中B4平面环的半芳香性

选用6-311++G(3df,2p)基组,在二级微扰的理论下,对四角锥形结构化合物BeB4X4(X=H,F,Cl),HBB4H4与BB4H4+的分子振动频率,及原子间的相互作用进行了计算,作用能的计算使用了CCSD(T)方法。结果显示HBB4H4与BB4H4+是违反韦德规则的另两个特例,它们表现稳定的原因与芳香性有关。     

室温下合成纺锤形貌六方相NaLnF_4(Ln=Nd,Sm,Eu,Gd,Tb)纳米颗粒

室温下合成长250nm,宽100nm的纺锤形貌六方相的NaNdF4。NaEuF4,NaSmF4,NaGdF4和NaTbF4也用同样的方法获得。产物用XRD,TEM,HRTEM,FESEM和PL进行表征。PL光谱显示合成的NaEuF4的激发波长是394nm。NaEuF4有4个特征发射谱带,分别是591,615,650和681nm。     

离子液体的组成及溶剂性质与木瓜蛋白酶催化特性的关系

离子液体的组成及溶剂性质对木瓜蛋白酶催化D,L-对羟基苯甘氨酸甲酯不对称水解反应有重要的影响. 木瓜蛋白酶在含CnMIm·BF4(n=2~6)介质中表现出较高的活性、对映体选择性及稳定性, 而在含有C4MIm·HSO4, C4MIm·Cl, C4MIm·NO3, C4MIm·CH3COO的介质中表现较低的对应值. 在含有CnMIm·BF4(n=2~6)的介质中, 酶活性随离子液体的极性增大而提高, 但在含有C4MIm·HSO4, C4MIm·Cl, C4MIm·NO3, C4MIm·CH3COO的介质中随离子液体的极性增大反而降低. 木瓜蛋白酶的对映体选择性和稳定性均随着离子液体的疏水性增大而提高. 荧光分析结果表明, 离子液体对酶分子构象具有显著的影响. 在CnMIm·BF4(n=2~6)的介质中, 木瓜蛋白酶的最大荧光发射波长(λmax)均蓝移, 而在含有C4MIm·HSO4, C4MIm·Cl, C4MIm·NO3或C4MIm·CH3COO的介质中, λmax均红移. 与CnMIm·BF4(n=2~6)相比, 在C4MIm·HSO4, C4MIm·Cl, C4MIm·NO3或C4MIm·CH3COO中, 酶分子构象的变化较大, 暴露的疏水区域较多.     

C3N4/BiVO4/Cu2O复合材料用于纯水中CO2光还原为甲醇

采用分步合成方法将Cu2O纳米颗粒原位还原组装到C3N4/BiVO4表面,设计并合成了 C3N4/BiVO4/Cu2O复合材料.在该过程中,首先将具有光氧化能力的BiVO4与C3N4复合制备出C3N4/BiVO4复合物,进一步通过原位合成法在C3N4/BiVO4复合物表面沉积Cu2O纳米颗粒制备出C3N4/BiVO4/...     

E_4~(2-),[CoE_4]~+和[P_4CoE_4]~-(E=N～Bi)结构和芳香性的理论预测

用密度泛函理论杂化密度泛函B3LYP方法研究了E24-,[CoE4]+和[P4CoE4]-(E=N,P,As,Sb,Bi)几何结构、键能及芳香性.结果表明,E42-,[CoE4]+和[P4CoE4]-的基态结构分别具有D4h,C4v和C4v(交错型)对称性.三明治配合物中,金属与配体间存在σ,π和δ三种成键方式,P4与E4间相互影响较小.E4对P4中的P—P键长影响随着N,P,As,Sb,Bi顺序逐渐变长,中心Co离子与E4间的键合能随N,P,As,Bi,Sb的顺序增大.N42-的环外具有弱芳香性,其它E42-环中心及环外均为反芳香性.除[CoN4]+外,其它[CoE4]+中的E4环均具有较强的中心和内芳香性及弱的外反芳香性.[P4CoE4]-中的P4和E4均具有较大的中心、内和外芳香性,且P4环芳香性随N,P,As,Sb,Bi顺序逐渐递增.     

Screening and Identification of a Targeting Peptide to nGLP-1R from Phage Display Peptide Library

<正>In order to provide the structure information for designing new exendin-4 analogues,a phage display peptide library was screened by targeting the N-terminal extracellular domain of GLP-1R(nGLP-1R).After four rounds of selection,nine sequences were obtained,four of them have higher affinity for nGLP-1R than the others.We chose two of them named X and Y peptides.Isletβ-cell proliferation assay suggested that X and Y peptides didn't have any activity to increase isletβ-cell proliferation.In other words,X and Y peptides were not agonists to GLP-1R.However, the conservative motifs of X and Y peptides provided us useful information to design new exendin-4 analogues.     

Effective synthesis of cyclic peptide yunnanin C and analogues via Ser/Thr ligation (STL)-mediated peptide cyclization

Cyclic peptide yunnanin C isolated from the root of Stellaria yunnanensis was efficiently synthesized in which the linear peptide was prepared by Boc-SPPS and the cyclization was realized by serine/threonine ligation (STL)-mediated cyclization. In addition, nine yunnanin C analogues, including mutations of Tyr7Gly, Tyr7Val, Tyr7Pro, Tyr7Phe, Ser1Thr, Pro2Val, Gly5Pro, Phe6Ala and Ile4Ala, were prepared in the same fashion. Here, we demonstrated that STL-mediated peptide cyclization could be an effective approach to construct cyclic peptides. Except that proline at the C-terminus could retard the cyclization process, cyclization of yunnanin C analogues with various C-terminal amino acids proceeded with fast cyclization rate (<4 h) and only trace amount of dimers (<5%) at a working concentration of 5 mM.     

Nucleation of beta-hairpin structures with cis amide bonds in E-vinylogous proline-containing peptides

Synthesis and conformational studies of peptides containing the E-vinylogous prolines 1 (VPro1) and 2 (VPro2), Boc-Ala-Val-VPro1-Xaa-Leu-OMe (3, Xaa = Gly; 4, Xaa = Phe), Boc-Ala-Val-VPro2-Xaa-Leu-OMe (5, Xaa = Gly; 6, Xaa = Phe), Boc-Leu-Ile-Val-VPro1-Xaa-Leu-OMe (7, Xaa = Gly; 8, Xaa = Phe), and Boc-Leu-Ile-Val-VPro2-Xaa-Leu-OMe (9, Xaa = Gly; 10, Xaa = Phe), were carried out. It has been shown that both VPro1 and VPro2 lead to the formation of 12-membered intramolecularly hydrogen bonded structures very similar to type VI beta-turns with a cis Xaa-VPro amide bond in the major conformers in all the peptides 3-10, resulting in the nucleation of beta-hairpin type structures in these molecules in CDCl(3).     

Trypsin inhibiting material from Ascaris lumbricoides var. suum. I. Preparation of pure trypsin inhibitors

The purification of a trypsin inhibitor from Ascaris lumbricoides var. suum is described. The electrophoretically pure preparation which inhibits trypsin in a specific manner is a relatively small peptide containing 5 Asp, 4 Thr, 1 Ser, 11 Glu, 6 Pro, 6 Gly, 5 Ala, 2 Val, 10 (Cys)_1/2, 3 Ile, 2 Phe, 7 Lys, 3 Arg and 1 Try.     

托品酮衍生物的合成及抗糖尿病活性

从6-羟基托品酮出发,经过羟基的乙酰基化和苯甲酰基化,再通过还原氨化高效地得到含有活泼胺基的2个母核化合物。 2个母核化合物与不同的酰氯反应,得到一系列托品酮衍生物。 该衍生物经过体外过氧化物酶增生因子活化受体γ亚型（PPARγ）激活、二肽基肽酶Ⅳ （DPP-Ⅳ）抑制实验,发现多数化合物对DPP-Ⅳ显示抑制活性,其中2个化合物(3 μmol/L DMSO溶液)对DPP-Ⅳ抑制率超过30%。     

Association of （S）-Isoserine Derivatives and 2,2,4-Trimethyl-3-hydroxy-4- cyclohexenecarboxylate

IntroductionOptimization of leading structures is an importantsector in the study and exploitation of medicine, andthe association of 2,2,4-trimethyl-3-hydroxyl-cyclohex-4-enecarboxylic acid (1) and isoserine derivatives isone of the best methods for the …     

Protein plasticity: a single amino acid substitution in the Saccharomyces cerevisiae oxidosqualene-lanosterol cyclase generates protosta-13(17),24-dien-3beta-ol, a rearrangement product

To provide insights into the structure-function relationships of oxidosqualene-lanosterol cyclase (ERG7) from Saccharomyces cerevisiae, the Phe699 was exchanged against hydrophilic polar uncharged residues Ser, Thr, Cys, Gln, and Tyr to characterize its product profile and functional role in ERG7 activity. Among the substitutions, only the ERG7(F699T) mutant produced novel protosta-13(17),24-dien-3beta-ol as the sole truncated rearrangement product. The results suggest that Phe699Thr mutation is likely to affect the C-17 cation stabilization during the rearrangement process.     

Identification of Dipeptidyl Peptidase-4 and α-Amylase Inhibitors from Melicope glabra (Blume) T. G. Hartley (Rutaceae) Using Liquid Chromatography Tandem Mass Spectrometry,In Vitro and In Silico Methods

The present study investigated the antidiabetic properties of the extracts and fractions from leaves and stem bark of M. glabra based on dipeptidyl peptidase-4 (DPP-4) and α-Amylase inhibitory activity assays. The chloroform extract of the leaves was found to be most active towards inhibition of DPP-4 and α-Amylase with IC₅₀ of 169.40 μg/mL and 303.64 μg/mL, respectively. Bioassay-guided fractionation of the leaves’ chloroform extract revealed fraction 4 (CF4) as the most active fraction (DPP-4 IC₅₀: 128.35 μg/mL; α-Amylase IC₅₀: 170.19 μg/mL). LC-MS/MS investigation of CF4 led to the identification of trans-decursidinol (1), swermirin (2), methyl 3,4,5-trimethoxycinnamate (3), renifolin (4), 4′,5,6,7-tetramethoxy-flavone (5), isorhamnetin (6), quercetagetin-3,4′-dimethyl ether (7), 5,3′,4′-trihydroxy-6,7-dimethoxy-flavone (8), and 2-methoxy-5-acetoxy-fruranogermacr-1(10)-en-6-one (9) as the major components. The computational study suggested that (8) and (7) were the most potent DPP-4 and α-Amylase inhibitors based on their lower binding affinities and extensive interactions with critical amino acid residues of the respective enzymes. The binding affinity of (8) with DPP-4 (−8.1 kcal/mol) was comparable to that of sitagliptin (−8.6 kcal/mol) while the binding affinity of (7) with α-Amylase (−8.6 kcal/mol) was better than acarbose (−6.9 kcal/mol). These findings highlight the phytochemical profile and potential antidiabetic compounds from M. glabra that may work as an alternative treatment for diabetes.     

FBXW7-mediated ERK3 degradation regulates the proliferation of lung cancer cells

Extracellular signal-regulated kinase 3 (ERK3) is an atypical member of the mitogen-activated protein kinase (MAPK) family, members of which play essential roles in diverse cellular processes during carcinogenesis, including cell proliferation, differentiation, migration, and invasion. Unlike other MAPKs, ERK3 is an unstable protein with a short half-life. Although deubiquitination of ERK3 has been suggested to regulate the activity, its ubiquitination has not been described in the literature. Here, we report that FBXW7 (F-box and WD repeat domain-containing 7) acts as a ubiquitination E3 ligase for ERK3. Mammalian two-hybrid assay and immunoprecipitation results demonstrated that ERK3 is a novel binding partner of FBXW7. Furthermore, complex formation between ERK3 and the S-phase kinase-associated protein 1 (SKP1)-cullin 1-F-box protein (SCF) E3 ligase resulted in the destabilization of ERK3 via a ubiquitination-mediated proteasomal degradation pathway, and FBXW7 depletion restored ERK3 protein levels by inhibiting this ubiquitination. The interaction between ERK3 and FBXW7 was driven by binding between the C34D of ERK3, especially at Thr417 and Thr421, and the WD40 domain of FBXW7. A double mutant of ERK3 (Thr417 and Thr421 to alanine) abrogated FBXW7-mediated ubiquitination. Importantly, ERK3 knockdown inhibited the proliferation of lung cancer cells by regulating the G₁/S-phase transition of the cell cycle. These results show that FBXW7-mediated ERK3 destabilization suppresses lung cancer cell proliferation in vitro.Subject terms: Protein quality control, Ubiquitylation     

天花粉蛋白的化学 III:溴化氰降解片段CBa的氨基酸顺序

The results from the study on the separation, purification, amino acid composition and amino acid sequence of CBa, one of the four CNBr degradation fragments of crystalline trichosanthin, are presented. Its amino acid composition is: Asp3, Thr2, Ser2, Hse1, Glu2, Gly2, Ala6, Val1, Tyr3, Phe3, Lys2, Arg1. The sequence of the CBa is Gly-Tyr-Arg-Ala-Gly-Asp-Thr-Ser- Tyr-Phe-Phe-Asn-Glu-Ala-Ser-Ala-Thr-Glu-Ala-Ala-Lys-Tyr-Val- Phe-Lys-Asp-Ala-Hso.