Less is More:Design of a Highly Stable Disulfide-Deleted Mutant of Analgesic Cyclic α-Conotoxin Vc1.

来源 :第八届国际分子模拟与信息技术应用学术会议 | 被引量 : 0次 | 上传用户:sprinia
下载到本地 , 更方便阅读
声明 : 本文档内容版权归属内容提供方 , 如果您对本文有版权争议 , 可与客服联系进行内容授权或下架
论文部分内容阅读
  Cyclic α-conotoxin Vc1.1(cVc1.1)is an orally active peptide with analgesic activity in rat models of neuropathic pain.It has two disulfide bonds,which can have three different connectivities,one of which is the native and active form.In this study we used computational modeling and nuclear magnetic resonance to design a disulfide-deleted mutant of cVc1.1,[C2H,C8F]cVc1.1,which has a larger hydrophobic core than cVc1.1 and,potentially,additional surface salt bridge interactions.The new variant,hcVc1.1,has similar structure and serum stability to cVci.i and is highly stable at a wide range of pH and temperatures.Remarkably,hcVc1.1 also has similar selectivity to cVc1.1,as it inhibited recombinant human αgα10 nicotinic acetylcholine receptor-mediated currents with an IC50 of 13μM and rat N-type(Cav2.2)and recombinant human Cav2.3 calcium channels via GABAB receptor activation,with an IC50 of-goo pM.Compared to cVc1.1,the potency of hcVc1.1 is reduced three-fold at both analgesic targets,whereas previous attempts to replace Vc1.1 disulfide bonds by non-reducible dicarba linkages resulted in at least 30-fold decreased activity.Because it has only one disulfide bond,hcVc1.1 is not subject to disulfide bond shuffling and does not form multiple isomers during peptide synthesis.
其他文献
The introduction of INF inhibitors has revolutionized the treatment of some chronic inflammatory diseases,e.g.,rheumatoid arthritis and Crohns disease.However,immunogenics ty is one of the important m
Motivation: One of the most promising applications of biosynthetic methods is to produce chemical products of high value from the ready-made chemicals.To explore the biosynthetic potentials of a chemi
会议
Interfcrence wich dynamic equilibrium of microtubulc-tubulin has provcn to be a uscful tactics in the clinic.Based on investigation into the structure-activity relationship(SAR)studies of tuhulin poly
Histone deacetylases(HDACs)are an important class of drug targets for the treatment of cancers,neurodegenerative diseases,and other types of diseases.Virtual screening(VS)has become fairly effective a
会议
Uncoupling protein 1(UCP1)plays an important role in promoting brown adipose tissue formation and strengthening function of increasing energy expenditure.Thus,activation of UCP1 has become an appealin
基于TKX-50的晶胞参数和主要生长面及共晶的形成原理,构建了TKX-50/ε-CL-20共晶结构模型.运用分子动力学模拟,基于平衡结构进行径向分布函数(RDF)和X射线粉末衍射(XRD)图谱分析以及模型能量计算.根据径向分布函数研究,TKX-50/ε-CL-20共晶模型中分子间存在较强的氢键作用力和范德华作用力;根据XRD谱图分析,TKX-50/ε-CL-20共晶衍射峰较纯组分TKX-50和ε-
As a type Ⅱ or Ⅲ transmembrane glycoprotein,human CD38 is ubiquitously expressed in all mammalian tissues.CD38 is a multi-functional enzyme and a member of the ADP-ribosyl cyclase family,and it cataly
plekstrin homology(PH)domains share low sequence identities But extremely conserved structures.They have been found in many proteins for cellular signal-dependent membrane targeting by binding inosito
会议
文中用合成一系列表面修饰铜物种和碳颗粒修饰的二氧化钛催化剂并进行了晶体结构,形貌和电子结构表征.表征结果显示存在于二氧化钛表面的铜物种和碳颗粒抑制了载流子的复合,延长了光生载流子的寿命,增强了可见光吸收,因此提升了光催化还原二氧化碳生成甲烷的催化活性.
Fullerene and its derivatives show promising prospects for applications in a vast array of biological systems.A key aspect concerning their biomedical applications is how they interact with proteins f