排序方式: 共有649条查询结果,搜索用时 15 毫秒
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Francine Z Marques Simon PR Romaine Matthew Denniff James Eales John Dormer Ingrid M Garrelds Lukasz Wojnar Katarzyna Musialik Barbara Duda-Raszewska Bartlomiej Kiszka Magdalena Duda Brian J Morris Nilesh J Samani AH Jan Danser Pawel Bogdanski Ewa Zukowska-Szczechowska Fadi J Charchar Maciej Tomaszewski 《Molecular medicine (Cambridge, Mass.)》2015,21(1):739-748
MicroRNA-181a binds to the 3′ untranslated region of messenger RNA (mRNA) for renin, a rate-limiting enzyme of the renin-angiotensin system. Our objective was to determine whether this molecular interaction translates into a clinically meaningful effect on blood pressure and whether circulating miR-181a is a measurable proxy of blood pressure. In 200 human kidneys from the TRANScriptome of renaL humAn TissuE (TRANSLATE) study, renal miR-181a was the sole negative predictor of renin mRNA and a strong correlate of circulating miR-181a. Elevated miR-181a levels correlated positively with systolic and diastolic blood pressure in TRANSLATE, and this association was independent of circulating renin. The association between serum miR-181a and systolic blood pressure was replicated in 199 subjects from the Genetic Regulation of Arterial Pressure of Humans In the Community (GRAPHIC) study. Renal immunohistochemistry and in situ hybridization showed that colocalization of miR-181a and renin was most prominent in collecting ducts where renin is not released into the systemic circulation. Analysis of 69 human kidneys characterized by RNA sequencing revealed that miR-181a was associated with downregulation of four mitochondrial pathways and upregulation of 41 signaling cascades of adaptive immunity and inflammation. We conclude that renal miR-181a has pleiotropic effects on pathways relevant to blood pressure regulation and that circulating levels of miR-181a are both a measurable proxy of renal miR-181a expression and a novel biochemical correlate of blood pressure. 相似文献
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Protein function annotation and rational drug discovery rely on the knowledge of binding sites for small organic compounds, and yet the quality of existing binding site predictors was never systematically evaluated. We assess predictions of ten representative geometry-, energy-, threading-, and consensus-based methods on a new benchmark data set that considers apo and holo protein structures with multiple binding sites for biologically relevant ligands. Statistical tests show that threading-based Findsite outperforms other predictors when its templates have high similarity with the input protein. However, Findsite is equivalent or inferior to some geometry-, energy-, and consensus-based methods when the similarity is lower. We demonstrate that geometry-, energy-, and consensus-based predictors benefit from the usage of holo structures and that the top four methods, Findsite, Q-SiteFinder, ConCavity, and MetaPocket, perform better for larger binding sites. Predictions from these four methods are complementary, and our simple meta-predictor improves over the best single predictor. 相似文献
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Russell RC Sufan RI Zhou B Heir P Bunda S Sybingco SS Greer SN Roche O Heathcote SA Chow VW Boba LM Richmond TD Hickey MM Barber DL Cheresh DA Simon MC Irwin MS Kim WY Ohh M 《Nature medicine》2011,17(7):845-853
Chuvash polycythemia is a rare congenital form of polycythemia caused by homozygous R200W and H191D mutations in the VHL (von Hippel-Lindau) gene, whose gene product is the principal negative regulator of hypoxia-inducible factor. However, the molecular mechanisms underlying some of the hallmark abnormalities of Chuvash polycythemia, such as hypersensitivity to erythropoietin, are unclear. Here we show that VHL directly binds suppressor of cytokine signaling 1 (SOCS1) to form a heterodimeric E3 ligase that targets phosphorylated JAK2 (pJAK2) for ubiquitin-mediated destruction. In contrast, Chuvash polycythemia-associated VHL mutants have altered affinity for SOCS1 and do not engage with and degrade pJAK2. Systemic administration of a highly selective JAK2 inhibitor, TG101209, reversed the disease phenotype in Vhl(R200W/R200W) knock-in mice, an experimental model that recapitulates human Chuvash polycythemia. These results show that VHL is a SOCS1-cooperative negative regulator of JAK2 and provide biochemical and preclinical support for JAK2-targeted therapy in individuals with Chuvash polycythemia. 相似文献
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Karanicolas J Corn JE Chen I Joachimiak LA Dym O Peck SH Albeck S Unger T Hu W Liu G Delbecq S Montelione GT Spiegel CP Liu DR Baker D 《Molecular cell》2011,42(2):250-260
The de novo design of protein-protein interfaces is a stringent test of our understanding of the principles underlying protein-protein interactions and would enable unique approaches to biological and medical challenges. Here we describe a motif-based method to computationally design protein-protein complexes with native-like interface composition and interaction density. Using this method we designed a pair of proteins, Prb and Pdar, that heterodimerize with a Kd of 130 nM, 1000-fold tighter than any previously designed de novo protein-protein complex. Directed evolution identified two point mutations that improve affinity to 180 pM. Crystal structures of an affinity-matured complex reveal binding is entirely through the designed interface residues. Surprisingly, in the in vitro evolved complex one of the partners is rotated 180° relative to the original design model, yet still maintains the central computationally designed hotspot interaction and preserves the character of many peripheral interactions. This work demonstrates that high-affinity protein interfaces can be created by designing complementary interaction surfaces on two noninteracting partners and underscores remaining challenges. 相似文献
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High-affinity, peptide-specific T cell receptors can be generated by mutations in CDR1, CDR2 or CDR3
Chlewicki LK Holler PD Monti BC Clutter MR Kranz DM 《Journal of molecular biology》2005,346(1):223-239
The third complementarity-determining regions (CDR3s) of antibodies and T cell receptors (TCRs) have been shown to play a major role in antigen binding and specificity. Consistent with this notion, we demonstrated previously that high-affinity, peptide-specific TCRs could be generated in vitro by mutations in the CDR3alpha region of the 2C TCR. In contrast, it has been argued that CDR1 and CDR2 are involved to a greater extent than CDR3s in the process of MHC restriction, due to their engagement of MHC helices. Based on this premise, we initiated the present study to explore whether higher affinity TCRs generated through mutations in these CDRs or other regions would lead to significant reductions in peptide specificity (i.e. the result of greater binding energy gained through interactions with major histocompatibility complex (MHC) helices). Yeast-display technology and flow sorting were used to select high-affinity TCRs from libraries of CDR mutants or random mutants. High-affinity TCRs with mutations in the first residue of the Valpha, CDR1, CDR2, or CDR3 were isolated. Unexpectedly, every TCR mutant, including those in CDR1 and CDR2, retained remarkable peptide specificity. Molecular modeling of various mutants suggested that such exquisite specificity may be due to: (1) enhanced electrostatic interactions with key peptide or MHC residues; or (2) stabilization of CDRs in specific conformations. The results indicate that the TCR is positioned so that virtually every CDR can contribute to the antigen-specificity of a T cell. The conserved diagonal docking of TCRs could thus orient each CDR loop to sense the peptide directly or indirectly through peptide-induced effects on the MHC. 相似文献
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Insulin-like growth factor - IGF-I is a small, 70 aminoacid mitogenic peptide, contributing to processes of growing, cancerogenesis, apoptosis, wound healing and many others. It constitutes so called 'somatotropic axis GH-IGF', composed of many other components. This axis is responsible for regulation of metabolic processes, and its proper functioning conditions organism's homeostasis. Presented work describes concise review of publications concerning IGF-I structure, function, expression and proteins affecting its activity, synthesis and circulation. 相似文献