Heat shock proteins(Hsps)are a family of abundantly expressed ATP-dependent chaperone proteins.Hsp90 is an eminent member of Hsp family.Thus far,two primary functions have been described for Hsp90:first,as a regulator...Heat shock proteins(Hsps)are a family of abundantly expressed ATP-dependent chaperone proteins.Hsp90 is an eminent member of Hsp family.Thus far,two primary functions have been described for Hsp90:first,as a regulator of conformational change of some protein kinases and nuclear hormone receptors,and the other as an indispensable factor in cellular stress response.Hsp90 has an essential number of interaction proteins since it participates in almost every biological process and its importance is self-evident.Hsp90 has an inextricable relationship in the pathogenesis of cancer,especially in the proliferation and irradiation of cancer cells,thus being a notable cancer target.Since the discovery of geldanamycin,the first inhibitor of Hsp90,from the bacterial species Streptomyces hygroscopicus,even more attention has been focused toward Hsp90.Many structure-based inhibitors of Hsp90 have been designed to develop an innovative method to defeat cancer.However,already designed inhibitors have various deficiencies,such as hepatotoxicity,poor aqueous solubility,instability,and non-ideal oral bioavailability.Based on the aforementioned reasons and to achieve an optimal performance and fewer side effects,we designed a novel inhibitor of Hsp90,called FS5,and resolved the crystal structure of the Hsp90^N-FS5 complex(1.65 A°,PDB code 5XRB).Furthermore,we compared the complexes Hsp90^N,Hsp90^N-GDM,and Hsp90^N-ATP and suggest that the inhibitor FS5 may compete with ATP for binding to Hsp90,which can be regarded as a potential strategy for the development of novel cancer drugs in the future.展开更多
The in-plane effective 90°magnetization rotation of Co_(2) FeAl thin film grown on PMN-PT substrate induced by the electric field is investigated at room temperature.The magnetic hysteresis loops under different ...The in-plane effective 90°magnetization rotation of Co_(2) FeAl thin film grown on PMN-PT substrate induced by the electric field is investigated at room temperature.The magnetic hysteresis loops under different positive and negative electric fields are obtained,which reveals remanent magnetization can be mediated by the electric field.Moreover,under positive electric fields,the obvious 90°magnetization rotation can be observed,while remanent magnetization is nearly unchanged under negative electric fields.The result is consistent with the electric field dependence of effective magnetic field,which can be attributed to the piezostrain effect in Co_(2) FeAl/PMN-PT structure.In addition,the piezostrain-mediated 90°magnetization rotation can be demonstrated by the result of resonance field changing with electric field in the measurement of ferromagnetic resonance,which is promising for the design of future multiferroic devices.展开更多
Heat shock protein 90(Hsp90) can promote growth and proliferation of cancer cells by helping in folding, conformational maturation, and activation of various client proteins. Therefore, Hsp90 has been paid more attent...Heat shock protein 90(Hsp90) can promote growth and proliferation of cancer cells by helping in folding, conformational maturation, and activation of various client proteins. Therefore, Hsp90 has been paid more attention to as an anticancer drug target. Reported Hsp90 inhibitors have several limitations such as poor solubility, limited bioavailability, and hepatotoxicity. Here, a novel small inhibitor RJ19 has been designed using fragment-based drug discovery and synthesized. Additionally, a crystal structure of Hsp90 N-RJ19 was determined by X-ray diffraction(resolution limit, 2.0 A, PDB code 4 L90). The crystal structure of Hsp90 N-RJ19 was analyzed in detail and compared with that of native Hsp90 N, Hsp90 N-ATP, and Hsp90 N-GDM,respectively. It was indicated that RJ19 interacted with Hsp90~N at the ATP-binding pocket, which suggests that RJ19 may replace nucleotides to bind with Hsp90~N to result in chaperone function failure of Hsp90. RJ19, therefore, has emerged as a promising anticancer lead compound. Rearrangement and displacement of L2 Loop in Hsp90~N-RJ 19 play a key role in the function failure, which also makes the pocket wider and longer facilitating structure modification of RJ19 later. The complex crystal structure and interaction between RJ19 and Hsp90~N provide a rational basis for the design and optimization of novel anticancer drugs.展开更多
基金supported by the Open Project of Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases,Ministry of Education(No.XN201904)Gannan Medical University(No.QD201910)+1 种基金the National Natural Science Foundation of China(Nos.31770795 and 31971043)the Jiangxi Province Natural Science Foundation(No.20181ACB20014)
文摘Heat shock proteins(Hsps)are a family of abundantly expressed ATP-dependent chaperone proteins.Hsp90 is an eminent member of Hsp family.Thus far,two primary functions have been described for Hsp90:first,as a regulator of conformational change of some protein kinases and nuclear hormone receptors,and the other as an indispensable factor in cellular stress response.Hsp90 has an essential number of interaction proteins since it participates in almost every biological process and its importance is self-evident.Hsp90 has an inextricable relationship in the pathogenesis of cancer,especially in the proliferation and irradiation of cancer cells,thus being a notable cancer target.Since the discovery of geldanamycin,the first inhibitor of Hsp90,from the bacterial species Streptomyces hygroscopicus,even more attention has been focused toward Hsp90.Many structure-based inhibitors of Hsp90 have been designed to develop an innovative method to defeat cancer.However,already designed inhibitors have various deficiencies,such as hepatotoxicity,poor aqueous solubility,instability,and non-ideal oral bioavailability.Based on the aforementioned reasons and to achieve an optimal performance and fewer side effects,we designed a novel inhibitor of Hsp90,called FS5,and resolved the crystal structure of the Hsp90^N-FS5 complex(1.65 A°,PDB code 5XRB).Furthermore,we compared the complexes Hsp90^N,Hsp90^N-GDM,and Hsp90^N-ATP and suggest that the inhibitor FS5 may compete with ATP for binding to Hsp90,which can be regarded as a potential strategy for the development of novel cancer drugs in the future.
基金the National Natural Science Foundation of China(Grant Nos.51901163 and 61903280)the Foundation of Wuhan Textile University(Grant Nos.193128 and 205033).
文摘The in-plane effective 90°magnetization rotation of Co_(2) FeAl thin film grown on PMN-PT substrate induced by the electric field is investigated at room temperature.The magnetic hysteresis loops under different positive and negative electric fields are obtained,which reveals remanent magnetization can be mediated by the electric field.Moreover,under positive electric fields,the obvious 90°magnetization rotation can be observed,while remanent magnetization is nearly unchanged under negative electric fields.The result is consistent with the electric field dependence of effective magnetic field,which can be attributed to the piezostrain effect in Co_(2) FeAl/PMN-PT structure.In addition,the piezostrain-mediated 90°magnetization rotation can be demonstrated by the result of resonance field changing with electric field in the measurement of ferromagnetic resonance,which is promising for the design of future multiferroic devices.
基金supported by the National Natural Science Foundation of China(Nos.31401185 and 81402850)the Introduced talents Foundation of Xi'an Medical University(No.2015 RCYJ 01)
文摘Heat shock protein 90(Hsp90) can promote growth and proliferation of cancer cells by helping in folding, conformational maturation, and activation of various client proteins. Therefore, Hsp90 has been paid more attention to as an anticancer drug target. Reported Hsp90 inhibitors have several limitations such as poor solubility, limited bioavailability, and hepatotoxicity. Here, a novel small inhibitor RJ19 has been designed using fragment-based drug discovery and synthesized. Additionally, a crystal structure of Hsp90 N-RJ19 was determined by X-ray diffraction(resolution limit, 2.0 A, PDB code 4 L90). The crystal structure of Hsp90 N-RJ19 was analyzed in detail and compared with that of native Hsp90 N, Hsp90 N-ATP, and Hsp90 N-GDM,respectively. It was indicated that RJ19 interacted with Hsp90~N at the ATP-binding pocket, which suggests that RJ19 may replace nucleotides to bind with Hsp90~N to result in chaperone function failure of Hsp90. RJ19, therefore, has emerged as a promising anticancer lead compound. Rearrangement and displacement of L2 Loop in Hsp90~N-RJ 19 play a key role in the function failure, which also makes the pocket wider and longer facilitating structure modification of RJ19 later. The complex crystal structure and interaction between RJ19 and Hsp90~N provide a rational basis for the design and optimization of novel anticancer drugs.
