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研究领域

1.蛋白质在去折叠状态下的结构 大家都知道的疯牛病,它是由一种称为Prion的蛋白质感染引起的,这种蛋白质也可以感染人而引起神经系统疾病。Prion的致病已被1997年诺贝尔奖获得者普鲁辛纳(Stanley B. Prusiner)证明不是来自基因的变化,致病蛋白Prion 导致正常蛋白 Prion 转变为致病的折叠状态是通过蛋白分子间的作用而感染!由于蛋白质折叠异常而造成分子聚集甚至沉淀或不能正常转运到位所引起的疾病还有老年性痴呆症、囊性纤维病变、家族性高胆固醇症、家族性淀粉样蛋白症、某些肿瘤、白内障等等。蛋白质在折叠状态下的结构可以通过晶体衍射和NMR及其它低分辨率方法获得;然而蛋白质在去折叠状态下的结构一直以来都无法得出明确的结论。较为公认的猜想是:各种二级结构(α 螺旋和 β 折叠及其它二级结构,随机缠绕Random Coil)并存于去折叠状态下,其中没有任何一种二级结构占绝对多数。我们设计并合成了不同同位素标记的由丙氨酸(Ala)组成的七肽,通过NMR和CD测试和分析发现此肽是以PII (Polyproline II 螺旋)为主而存在的(既不是 α 螺旋,又不是 β 折叠,也不是各种结构的混合物),这间接说明蛋白质在去折叠状态下有可能是以 PII 为主的结构而存在。在引申工作中, 我们发现 PII 结构不仅存在于丙氨酸肽中, 而且存在于所有19种氨基酸以 GGXGG 为代表的短肽中, 同时我们还发现, 19种氨基酸形成PII的倾向性与它们形成 β 二级结构的倾向性反相关。这项工作对于了解蛋白质其折叠过程中的起始状态结构具有重要的基础性贡献,同时对于理解蛋白质错误折叠(而引起相关疾病)其分子机制亦有重大价值。相关工作前后三次发表在 Proceedings of the National Academy of Sciences USA 杂志并得到高度评价。我们将继续研究蛋白质在去折叠状态下为什么以PII结构存在。 2. 抗菌肽和树枝状多肽药物的研究和开发 许多细菌和微生物通过变异及其它各种机制对各种常用抗生素产生抗药性;病菌的抗药性导致许多传染性疾病难以治愈; 最近发现的超级细菌是一个典型的例子。抗菌肽与常用抗生素相比,由于其杀菌的机制完全不同,对于各类抗药性病菌较为有效;另外,细菌一般不会对抗菌肽产生抗药性。基于目前对于抗菌肽杀菌机制的有限了解, 加之其成本及毒性等方面的因素, 抗菌肽的研究还不成熟。 树枝状多肽是一类特殊的多肽, 相对于通常链状多肽, 它们的形状象有很多分枝的树枝。这类分子作为抗菌肽、疫苗、药物运送载体及诊断分子试剂具有特殊的潜力。本实验室将设计并合成一系列包括树枝状肽的多肽,测试其抗菌活性及其它相关活性,希望能研发出某种多肽药物,同时从机制上加深理解其杀菌过程。

近期论文

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HE L, NAVARRO AE, SHI ZS* and KALLENBACH NR*; End Effects Influence Short Model Peptide Conformation;Journal of the American Chemical Society 134, 1571–1576, 2012. YOUNG AW, LIU ZG, ZHOU CH, TOTSINGAN F, JIWRAJKA N, SHI ZS* and KALLENBACH NR*; Structure and Antimicrobial Properties of Multivalent Short Peptides; Medicinal Chemistry Communications 2, 308–314, 2011. SHI ZS, ZHOU CH, LIU ZG, TOTSINGAN F, KALLENBACH NR; Amino Acid-Based Dendrimers “Amino Acids, Peptide and Proteins in Organic Chemistry Vol 4 - Protection Reactions, Medicinal Chemistry, Combinatorial Synthesis“ (Editor: Andrew B. Hughes, Wiley-VCH), 491-517, 2011. SHI ZS and KALLENBACH NR; Ramachandran Redux; Proceedings of the National Academy of Sciences USA 108, 3-4, 2011. HOU SY, ZHOU CH, LIU ZG, YOUNG AW, SHI ZS, REN DC and KALLENBACH NR; Antimicrobial dentrimer active against E coli biofilms; Bioorganic & Medicinal Chemistry Letters 19, 5478-5481, 2009. SHI ZS, RESING KA and AHN NG; Networks for the allosteric control of protein kinases; Current Opinion in Structural Biology 16, 686-692, 2006. SHI ZS, CHEN K, LIU ZG and KALLENBACH NR; Conformations of the backbone in unfolded proteins; Chemical Reviews 106, 1877-1897, 2006. SHI ZS, CHEN K, LIU ZG, SOSNICK TR and KALLENBACH NR; PII structure in the model peptides for unfolded proteins: studies on ubiquitin fragments and several alanine-rich peptides containing QQQ, SSS, FFF and VVV; Proteins: Structure Function and Bioinformatics 63, 312-321, 2006. SHI ZS, PETERSON RW and WAND AJ; New Reverse Micelle Surfactant Systems Optimized for High-Resolution NMR Spectroscopy of Encapsulated Proteins; Langmuir, 21, 10632–10637, 2005. SHI ZS, CHEN K, LIU ZG, NG A, BRACKEN WC and KALLENBACH NR; Polyproline II propensities from GGXGG reveal an anti-correlation with the beta-sheet scale; Proceedings of the National Academy of Sciences USA 102, 17964-17968, 2005. CHEN K, LIU ZG, ZHOU CH, SHI ZS and KALLENBACH NR; Neighbor Effect on PPII Conformation in Alanine Peptides; Journal of the American Chemical Society 127,10146–10147, 2005. PETERSON RW, POMETUN M, SHI ZS and WAND AJ; Novel surfactant mixtures for NMR spectroscopy of encapsulated proteins dissolved in low viscosity fluids; Protein Science 14, 2919-2921, 2005. LIU ZG, CHEN K, NG A, SHI ZS, WOODY RW and KALLENBACH NR; Solvent Dependence of PII Conformation in Model Alanine Peptides; Journal of the American Chemical Society 126, 15141–15150, 2004. DING L, CHEN K, SANTINI PA, SHI ZS and KALLENBACH NR; The Pentapeptide GGAGG Has PII Conformation; Journal of the American Chemical Society 125, 8092–8093, 2003. SHI ZS, OLSON CA, ROSE GD, BALDWIN RL and KALLENBACH NR; Polyproline II structure in a sequence of seven alanine residues;Proceedings of the National Academy of Sciences USA 99, 9190-9195, 2002. SHI ZS, OLSON CA and KALLENBACH NR;Cation-pi interaction in model α-helical peptides;Journal of the American Chemical Society 124, 3284-3291, 2002. SHI ZS, OLSON CA, KALLENBACH NR and SOSNICK TR; D/H amide isotope effect in model α-helical peptides; Journal of the American Chemical Society 124, 13994-13995, 2002. SHI ZS, KRANTZ BA, KALLENBACH NR and SOSNICK TR;Contribution of Hydrogen Bonding to Protein Stability Estimated from Isotope Effects;Biochemistry 41, 2120–2129, 2002. SHI ZS, WOODY RW and KALLENBACH NR;Is polyproline II the major backbone conformation in unfolded proteins? Advances in Protein Chemistry 62, 163-240, 2002. SHI ZS, OLSON CA, BELL AJ and KALLENBACH NR; CH···O H-bonding interaction between Phe & Glu side chains in α-helical peptides;Biophysical Chemistry 101-2, 267-279, 2002. SHI ZS, OLSON CA, BELL AJ and KALLENBACH NR;Polar side chain interactions stabilize α-helix structure: Complex salt bridges, cation-π and CH···O H-bonding interactions; Biopolymers 60, 366-380, 2001. OLSON CA, SHI ZS and KALLENBACH NR; Polar Interactions with Aromatic Side Chains in α-Helical Peptides: CH···O H-Bonding and Cation-π Interactions; Journal of the American Chemical Society 123, 6451–6452, 2001. SPEK EJ, OLSON CA, SHI ZS and KALLENBACH NR; Alanine is an intrinsic α-helix stabilizing amino acid; Journal of the American Chemical Society 121, 5571-5572, 1999.

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