The N-terminal domain of heat shock protein 90(Hsp90~N) is responsible for the catalytic activity of Hsp90.The reported inhibitors of Hsp90 bind to this domain and would inhibit tumor growth and progression. Here,we s...The N-terminal domain of heat shock protein 90(Hsp90~N) is responsible for the catalytic activity of Hsp90.The reported inhibitors of Hsp90 bind to this domain and would inhibit tumor growth and progression. Here,we synthesized FS23, a small molecule inhibitor of hsp90 and collected X-ray diffraction data of the complex crystal of Hsp90-FS23. High resolution X-ray crystallography shows that FS23 interacted with Hsp90 Nat the nucleotide binding cleft, and this suggests that FS23 may complete with nucleotides to bind to Hsp90~N. The crystal structure and the interaction between Hsp90 Nand FS23 suggest a rational basis for the design of novel antitumor drugs.展开更多
We have known since 1976 that cancer evolves clonally from one initiated<span style="font-family:;" "=""><span> normal human cell, the </span><i><span>first cell&...We have known since 1976 that cancer evolves clonally from one initiated<span style="font-family:;" "=""><span> normal human cell, the </span><i><span>first cell</span></i><span>. Today we see that this fact has been overshadowed from federal funding choice of the mutation theory (MT), which not yet has shown tumorigenesis-initiation in normal human cells. Our suggested, death signaled, stress model from time delayed S-period (replication slowness), causing repair instability from under-replicated lesions in repetitive DNAs, herein has the objective of revealing, significant literature support from a mini-review. We reasoned that early versus late S-period stress would </span><span>have different outcomes: early the slowness affecting mitotic slippage with</span> <span>diploid re-replication to 4n cells whereas late-S, with milder stress effect,</span><span> pro</span><span>ducing diploid cells. In cancer burden, near-half is diploid, but tetraploid</span><span> solid tumors have the attention. The initial 4n cells were special with orderly genomic reductive division to diploid first cells with measurable fitness-gain from hours-reduced total cell cycle time. Experimental data from Coxsakie-B3 virus infected normal fibroblasts, reiterated 4n cell production from </span><span>death-s</span><span>ignaled recovery-cells with progressive cell-phenotypic changes to polygon</span><span>al </span><span>and roundness cell-shapes, indistinguishable from diagnostic/prognostic </span><span>cancer </span><span>morphology. The 4n cells showed a self-inflicted 90</span></span><span style="font-family:;" "=""><span><span style="color:#4F4F4F;white-space:normal;background-color:#FFFFFF;"><span style="color:#4F4F4F;white-space:normal;background-color:#FFFFFF;">°</span></span></span><span> turn of the 4n nucleus</span></span><span style="font-family:;" "=""> <span>before division, affecting a perpendicular orientation of the fitness-gained</span><span> first cells relative to neighboring cells. In an illustrated cell cycle drawing with early and late S-period stress, it became clear that coding genes on borders of repair unstable satellite, repetitive DNA regions, could become mutated. We found these mutations to be tumor SMGs (significantly mutated genes). Evidential material was presented for loss of function genetics driving tumorigenesis to a parasitic lifestyle.</span></span>展开更多
本文对纯氮氮笼N_(90)(具有D3d对称性)的分子结构和能量在B3LYP/cc-p VDZ水平下进行计算研究。全面地解析了N_(90)分子的结构,并对它进行了Atoms In Molecule(AIM)分析。图形分析和数值分析结果表明,N_(90)分子内存在多个弱相互作用力...本文对纯氮氮笼N_(90)(具有D3d对称性)的分子结构和能量在B3LYP/cc-p VDZ水平下进行计算研究。全面地解析了N_(90)分子的结构,并对它进行了Atoms In Molecule(AIM)分析。图形分析和数值分析结果表明,N_(90)分子内存在多个弱相互作用力。随后本文论述了这种弱作用力与分子构型之间的相互联系,指出了分子内的弱相互作用力是纯氮大分子N_(90)的热力学稳定的一个重要因素。展开更多
基金Supported by National Natural Science Foundation of China(No.81402850)the Natural Science Basic Research Plan in Shaanxi Province of China(No.2015JM3114)+1 种基金the Introduced talents Foundation of Xi’an Medical University(No.2015 RCYJ01)the Doctorate Foundation of Xi’an Medical University(No.2015 DOC23)
文摘The N-terminal domain of heat shock protein 90(Hsp90~N) is responsible for the catalytic activity of Hsp90.The reported inhibitors of Hsp90 bind to this domain and would inhibit tumor growth and progression. Here,we synthesized FS23, a small molecule inhibitor of hsp90 and collected X-ray diffraction data of the complex crystal of Hsp90-FS23. High resolution X-ray crystallography shows that FS23 interacted with Hsp90 Nat the nucleotide binding cleft, and this suggests that FS23 may complete with nucleotides to bind to Hsp90~N. The crystal structure and the interaction between Hsp90 Nand FS23 suggest a rational basis for the design of novel antitumor drugs.
文摘We have known since 1976 that cancer evolves clonally from one initiated<span style="font-family:;" "=""><span> normal human cell, the </span><i><span>first cell</span></i><span>. Today we see that this fact has been overshadowed from federal funding choice of the mutation theory (MT), which not yet has shown tumorigenesis-initiation in normal human cells. Our suggested, death signaled, stress model from time delayed S-period (replication slowness), causing repair instability from under-replicated lesions in repetitive DNAs, herein has the objective of revealing, significant literature support from a mini-review. We reasoned that early versus late S-period stress would </span><span>have different outcomes: early the slowness affecting mitotic slippage with</span> <span>diploid re-replication to 4n cells whereas late-S, with milder stress effect,</span><span> pro</span><span>ducing diploid cells. In cancer burden, near-half is diploid, but tetraploid</span><span> solid tumors have the attention. The initial 4n cells were special with orderly genomic reductive division to diploid first cells with measurable fitness-gain from hours-reduced total cell cycle time. Experimental data from Coxsakie-B3 virus infected normal fibroblasts, reiterated 4n cell production from </span><span>death-s</span><span>ignaled recovery-cells with progressive cell-phenotypic changes to polygon</span><span>al </span><span>and roundness cell-shapes, indistinguishable from diagnostic/prognostic </span><span>cancer </span><span>morphology. The 4n cells showed a self-inflicted 90</span></span><span style="font-family:;" "=""><span><span style="color:#4F4F4F;white-space:normal;background-color:#FFFFFF;"><span style="color:#4F4F4F;white-space:normal;background-color:#FFFFFF;">°</span></span></span><span> turn of the 4n nucleus</span></span><span style="font-family:;" "=""> <span>before division, affecting a perpendicular orientation of the fitness-gained</span><span> first cells relative to neighboring cells. In an illustrated cell cycle drawing with early and late S-period stress, it became clear that coding genes on borders of repair unstable satellite, repetitive DNA regions, could become mutated. We found these mutations to be tumor SMGs (significantly mutated genes). Evidential material was presented for loss of function genetics driving tumorigenesis to a parasitic lifestyle.</span></span>
文摘本文对纯氮氮笼N_(90)(具有D3d对称性)的分子结构和能量在B3LYP/cc-p VDZ水平下进行计算研究。全面地解析了N_(90)分子的结构,并对它进行了Atoms In Molecule(AIM)分析。图形分析和数值分析结果表明,N_(90)分子内存在多个弱相互作用力。随后本文论述了这种弱作用力与分子构型之间的相互联系,指出了分子内的弱相互作用力是纯氮大分子N_(90)的热力学稳定的一个重要因素。
