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1. chinaXiv:201605.01405 [pdf]

Structure of Ljungan virus provides insight into genome packaging of this picornavirus

Zhu, Ling; Ren, Jingshan; Porta, Claudine; Kotecha, Abhay; Siebert, C. Alistair; Fry, Elizabeth E.; Stuart, David I.; Zhu, Ling; Porta, Claudine; Wenham, Hannah; Panjwani, Anusha; Knowles, Nick J.; Tuthill, Tobias J.; Wang, Xiangxi; Rao, Zihe; Ekstrom, Jens-Ola; Lindberg, A. Michael; Rao, Zihe; Stuart, David I.
Subjects: Biology >> Biophysics

Picornaviruses are responsible for a range of human and animal diseases, but how their RNA genome is packaged remains poorly understood. A particularly poorly studied group within this family are those that lack the internal coat protein, VP4. Here we report the atomic structure of one such virus, Ljungan virus, the type member of the genus Parechovirus B, which has been linked to diabetes and myocarditis in humans. The 3.78-angstrom resolution cryo-electron microscopy structure shows remarkable features, including an extended VP1 C terminus, forming a major protuberance on the outer surface of the virus, and a basic motif at the N terminus of VP3, binding to which orders some 12% of the viral genome. This apparently charge-driven RNA attachment suggests that this branch of the picornaviruses uses a different mechanism of genome encapsidation, perhaps explored early in the evolution of picornaviruses.

submitted time 2016-05-12 Hits1519Downloads871 Comment 0

2. chinaXiv:201605.01310 [pdf]

Molecular architecture of the ErbB2 extracellular domain homodimer

Hu, Shi; Guo, Huaizu; Qian, Weizhu; Hou, Sheng; Li, Bohua; Guo, Yajun; Hu, Shi; Guo, Huaizu; Qian, Weizhu; Hou, Sheng; Li, Bohua; Guo, Yajun; Hu, Shi; Sun, Yuna; Rao, Zihe; Hu, Shi; Sun, Yuna; Rao, Zihe; Lou, Zhiyong; Hu, Shi
Subjects: Biology >> Biophysics >> Oncology

Human epidermal growth factor receptors (HERs or ErbBs) play crucial roles in numerous cellular processes. ErbB2 is a key member of ErbB family, and its overexpression is recognized as a frequent molecular abnormality. In cancer, this overexpression correlates with aggressive disease and poor patient outcomes. Dimer-dependent phosphorylation is a key event for the signal transduction of ErbBs. However, the molecular mechanism of the dimerization of ErbB2 remains elusive. In the present work, we report the homodimer architecture of the ErbB2 extracellular domain (ECD) which is unique compared with other dimer-models of ErbBs. The structure of the ErbB2 ECD homodimer represents a "back to head" interaction, in which a protruding beta-hairpin arm in domain II of one ErbB2 protomer is inserted into a C-shaped pocket created by domains I-III of the adjacent ErbB2 protomer. This dimerized architecture and its impact on the phosphorylation of ErbB2 intracellular domain were further verified by a mutagenesis study. We also elucidated the different impacts of two clinically administered therapeutic antibodies, trastuzumab and pertuzumab, on ErbB2 dimerization. This information not only provides an understanding of the molecular mechanism of ErbBs dimerization but also elucidates ErbB2-targeted therapy at the molecular level.

submitted time 2016-05-11 Hits4210Downloads1456 Comment 0

3. chinaXiv:201605.01306 [pdf]

Structures of the yeast dynamin-like GTPase Sey1p provide insight into homotypic ER fusion

Yan, Liming; Wang, Wei; Rao, Zihe; Lou, Zhiyong; Sun, Sha; Shi, Juanming; Hu, Xiaoyu; Hu, Junjie; Sun, Sha; Shi, Juanming; Hu, Xiaoyu; Hu, Junjie; Rao, Zihe; Hu, Junjie; Wang, Wei; Wang, Shiyan; Su, Dan; Su, Dan; Rao, Zihe; Lou, Zhiyong
Subjects: Biology >> Biophysics >> Cell Biology

Homotypic membrane fusion of the endoplasmic reticulum is mediated by dynamin-like guanosine triphosphatases (GTPases), which include atlastin (ATL) in metazoans and Sey1p in yeast. In this paper, we determined the crystal structures of the cytosolic domain of Sey1p derived from Candida albicans. The structures reveal a stalk-like, helical bundle domain following the GTPase, which represents a previously unidentified configuration of the dynamin superfamily. This domain is significantly longer than that of ATL and critical for fusion. Sey1p forms a side-by-side dimer in complex with GMP-PNP or GDP/AlF4- but is monomeric with GDP. Surprisingly, Sey1p could mediate fusion without GTP hydrolysis, even though fusion was much more efficient with GTP. Sey1p was able to replace ATL in mammalian cells, and the punctate localization of Sey1p was dependent on its GTPase activity. Despite the common function of fusogenic GTPases, our results reveal unique features of Sey1p.

submitted time 2016-05-11 Hits1599Downloads980 Comment 0

4. chinaXiv:201605.01300 [pdf]

Hepatitis A virus and the origins of picornaviruses

Wang, Xiangxi; Gao, Qiang; Sun, Yao; Li, Xuemei; Rao, Zihe; Ren, Jingshan; Stuart, David I.; Fry, Elizabeth E.; Gao, Qiang; Yin, Weidong; Hu, Zhongyu; Wang, Junzhi; Rowlands, David J.; Rowlands, David J.; Stuart, David I.; Rao, Zihe; Rao, Zihe
Subjects: Biology >> Biophysics

Hepatitis A virus(HAV) remains enigmatic, despite 1.4 million cases worldwide annually(1). It differs radically from other picornaviruses, existing in an enveloped form(2) and being unusually stable, both genetically and physically(3), but has proved difficult to study. Here we report high-resolution X-ray structures for the mature virus and the empty particle. The structures of the two particles are indistinguishable, apart from some disorder on the inside of the empty particle. The full virus contains the small viral protein VP4, whereas the empty particle harbours only the uncleaved precursor, VP0. The smooth particle surface is devoid of depressions that might correspond to receptor-binding sites. Peptide scanning data extend the previously reported VP3 antigenic site4, while structure-based predictions(5) suggest further epitopes. HAV contains no pocket factor and can withstand remarkably high temperature and low pH, and empty particles are even more robust than full particles. The virus probably uncoats via a novel mechanism, being assembled differently to other picornaviruses. It utilizes a VP2 'domain swap' characteristic of insect picorna-like viruses(6,7), and structure-based phylogenetic analysis places HAV between typical picornaviruses and the insect viruses. The enigmatic properties of HAV may reflect its position as a link between 'modern' picornaviruses and the more 'primitive' precursor insect viruses; for instance, HAV retains the ability to move from cell-to-cell by transcytosis(8,9).

submitted time 2016-05-11 Hits1612Downloads1001 Comment 0

5. chinaXiv:201605.01253 [pdf]

Cyanohydrin as an Anchoring Group for Potent and Selective Inhibitors of Enterovirus 71 3C Protease

Zhai, Yangyang; Zhao, Xiangshuai; Cui, Zhengjie; Wang, Man; Li, Linfeng; Yang, Xi; Zeng, Debin; Liu, Ying; Shang, Luqing; Yin, Zheng; Zhai, Yangyang; Zhao, Xiangshuai; Cui, Zhengjie; Wang, Man; Li, Linfeng; Yang, Xi; Zeng, Debin; Liu, Ying; Shang, Luqing; Yin, Zheng
Subjects: Biology >> Biophysics

Cyanohydrin derivatives as enterovirus 71 (EV71) 3C protease (3C(pro)) inhibitors have been synthesized and assayed for their biochemical and antiviral activities. Compared with the reported inhibitors, cyanohydrins (1S,2S,2'S,5S)-16 and (1R,2S,2'S,5S)-16 exhibited significantly improved activity and attractive selectivity profiles against other proteases, which were a result of the specific interactions between the cyanohydrin moiety and the catalytic site of 3C(pro). Cyanohydrin as an anchoring group with high selectivity and excellent inhibitory activity represents a useful choice for cysteine protease inhibitors.

submitted time 2016-05-11 Hits1705Downloads1016 Comment 0

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