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161.
Riboswitches are metabolite-sensing RNAs, typically located in the non-coding portions of messenger RNAs, that control the synthesis of metabolite-related proteins. Here we describe a 2.05 angstroms crystal structure of a riboswitch domain from the Escherichia coli thiM mRNA that responds to the coenzyme thiamine pyrophosphate (TPP). TPP is an active form of vitamin B1, an essential participant in many protein-catalysed reactions. Organisms from all three domains of life, including bacteria, plants and fungi, use TPP-sensing riboswitches to control genes responsible for importing or synthesizing thiamine and its phosphorylated derivatives, making this riboswitch class the most widely distributed member of the metabolite-sensing RNA regulatory system. The structure reveals a complex folded RNA in which one subdomain forms an intercalation pocket for the 4-amino-5-hydroxymethyl-2-methylpyrimidine moiety of TPP, whereas another subdomain forms a wider pocket that uses bivalent metal ions and water molecules to make bridging contacts to the pyrophosphate moiety of the ligand. The two pockets are positioned to function as a molecular measuring device that recognizes TPP in an extended conformation. The central thiazole moiety is not recognized by the RNA, which explains why the antimicrobial compound pyrithiamine pyrophosphate targets this riboswitch and downregulates the expression of thiamine metabolic genes. Both the natural ligand and its drug-like analogue stabilize secondary and tertiary structure elements that are harnessed by the riboswitch to modulate the synthesis of the proteins coded by the mRNA. In addition, this structure provides insight into how folded RNAs can form precision binding pockets that rival those formed by protein genetic factors. 相似文献
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167.
Molecular basis for differences between human joints 总被引:8,自引:0,他引:8
The molecular program of a cell determines responses including induction or inhibition of genes for function and activity,
and this is true of the cells within articular cartilage, a major functional component of the joint. While our studies have
previously focussed on differences in the molecular programs of the cells within the superficial and deep zones, we have recently
begun to focus on relative differences between joints, such as the knee and ankle. In the human, these joints vary greatly
in their susceptibility to joint diseases, such as osteoarthritis (OA). We have predicted that there would be a molecular
basis for differences between joints that could lead to differences in susceptibility to OA, if inherent pathways locked into
the resident cells induce differences in their response to their environment. We have been able to show that there are differences
between the matrix components and water content; these properties correspond to a higher equilibrium modulus and dynamic stiffness
but lower hydraulic permeability and serve to make the ankle cartilage stiffer, slowing movement of molecules through the
cartilage. In addition to these biochemical differences in the cartilage matrix, we have also identified relative differences
in the strength of the response to stimulation of chondrocytes from knee and ankle. The stronger response of the knee chondrocytes
includes factors that increase damage to the cartilage matrix, such as a depression of matrix synthesis and increased enzyme
activity. This response by the knee chondrocytes results in enzyme damage to the matrix that the cells may not be able to
repair, while the weaker response of the ankle chondrocytes may allow the cells to repair their matrix damage. 相似文献
168.
Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex 总被引:39,自引:0,他引:39
Zheng N Schulman BA Song L Miller JJ Jeffrey PD Wang P Chu C Koepp DM Elledge SJ Pagano M Conaway RC Conaway JW Harper JW Pavletich NP 《Nature》2002,416(6882):703-709
SCF complexes are the largest family of E3 ubiquitin-protein ligases and mediate the ubiquitination of diverse regulatory and signalling proteins. Here we present the crystal structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF complex, which shows that Cul1 is an elongated protein that consists of a long stalk and a globular domain. The globular domain binds the RING finger protein Rbx1 through an intermolecular beta-sheet, forming a two-subunit catalytic core that recruits the ubiquitin-conjugating enzyme. The long stalk, which consists of three repeats of a novel five-helix motif, binds the Skp1-F boxSkp2 protein substrate-recognition complex at its tip. Cul1 serves as a rigid scaffold that organizes the Skp1-F boxSkp2 and Rbx1 subunits, holding them over 100 A apart. The structure suggests that Cul1 may contribute to catalysis through the positioning of the substrate and the ubiquitin-conjugating enzyme, and this model is supported by Cul1 mutations designed to eliminate the rigidity of the scaffold. 相似文献
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Parthenogenetic reptiles: New subjects for laboratory research 总被引:1,自引:0,他引:1
Summary Problems preventing establishment of laboratory colonies of parthenogenetic lizards have been solved. Now, productive colonies of these lizards, which have remarkably little genetic variation, can be readily established and used not only for research on parthenogenesis but also for many kinds of experiments for which reptile systems are desirable. Research colonies can provide valuable specimens while reducing the exploitation of natural populations.We thank José P. O. Rosado and George W. Foley for technical assistance and Richard G. Zweifel for specimens, ideas and support. 相似文献