Search

We have found, using a newly developed genetic method, a protein (named Cnu, for oriC-binding nucleoid-associated) that binds to a specific 26-base-pair sequence (named cnb) in the origin of replication of Escherichia coli, oriC. Cnu is composed of 71 amino acids (8.4 kDa) and shows extensive amino acid identity to a group of proteins belonging to the Hha/YmoA family. Cnu was previously discovered as a protein that, like Hha, complexes with H-NS in vitro. Our in vivo and in vitro assays confirm the results and further suggest that the complex formation with H-NS is involved in Cnu/Hha binding to cnb. Unlike the hns mutants, elimination of either the cnu or hha gene did not disturb the growth rate, origin content, and synchrony of DNA replication initiation of the mutants compared to the wild-type cells. However, the cnu hha double mutant was moderately reduced in origin content. The Cnu/Hha complex with H-NS thus could play a role in optimal activity of oriC.

A study was conducted to examine the dynamics of the pathogenic mutants (P101L and H186R), protective mutants (Q167R and Q218K), and wild-type mouse PrP(89?230) at pH 5.5 and 3.5. Findings suggested the possibility that the pathogenic or dominant negative mutations exert their effects on non-native intermediate.

An ensemble approach to the boundary element method that accurately predicts rotational tumbling time ([tau]c) for well-structured and rigid proteins by introducing two layers of molecular surfaces whose correlated velocities decay exponentially with distance is presented. The reliable prediction obtained by ([tau]c would help to detect intra- and intermolecular interactions and conformational switches between more ordered and less ordered states of the disordered segments.

In contrast to the highly mutagenic pyrimidine(6-4)pyrimidone photoproduct, its Dewar valence isomer (Dewar product) has low mutagenic potential and produces a broad range of mutations [LeClerc, J. E., Borden, A. & Lawrence, C. W. (1991) Proc. Natl. Acad. Sci. USA 88, 9685-9689]. To determine the origin of the mutagenic property of the Dewar product, we used experimental NMR restraints and molecular dynamics to determine the solution structure of a Dewar-lesion DNA decamer duplex. This DNA decamer duplex (DW/GA duplex) contains a mismatched base pair between the 3' T residue of the Dewar lesion (T6) and an opposed G residue (G15). The 3' T (T6) of the Dewar lesion formed stable hydrogen bonds with the opposing G15 residue. However, the helical bending and unwinding angles of the DW/GA duplex were much larger than those of a second duplex that contains the Dewar lesion and opposing A15 and A16 residues (DW/AA duplex). The DW/GA duplex showed poorer stacking interactions at the two bases of the Dewar product and at the adjacent A7[multiply by]T14 base pair than did the DW/AA duplex. These structural features imply that no thermal stability or conformational benefit is obtained by incorporating a G instead of an A opposite the 3' T of the Dewar lesion. These properties may thus facilitate the preferential incorporation of an A in accordance with the A rule during translesion replication and lead to the low frequency of 3' T[right arrow]C mutations observed at this site.

The use of NMR-derived chemical shiftsin protein structure determinationand prediction has received much attention, and, as such, many methodshave been developed to predict protein chemical shifts from three-dimensional(3D) coordinates. In contrast, little attention has been paid to predictingchemical shifts from RNA coordinates. Using the random forest machinelearning approach, we developed RAMSEY, which is capable of predicting both1H and protonated 13C chemicalshifts from RNA coordinates. In this report, we introduce RAMSEY,assess its accuracy, and demonstrate the sensitivity of RAMSEY-predictedchemical shifts to RNA 3D structure. [ABSTRACT FROM AUTHOR]

Presents information on a study which used experimental nuclear magnetic resonance restraints and molecular dynamics to determine the solution structure of a Dewar-lesion DNA decamer duplex. Structure determination; Hydrogen-binding feature at the Dewar lesion site; Methodology of the study; Results and discussion.

Tofacitinib, a Janus kinase (JAK) inhibitor used to treat rheumatoid arthritis, is metabolized through hepatic cytochrome P450 (CYP), specifically CYP3A1/2 and CYP2C11. Prolonged administration of rheumatoid arthritis medications is generally associated with an increased risk of renal toxicity. Loganin (LGN), an iridoid glycoside, has hepatorenal regenerative properties. This study investigates the potential of LGN to mitigate acute kidney injury (AKI) and its effects on the pharmacokinetics of tofacitinib in rats with cisplatin-induced AKI. Both intravenous and oral administration of tofacitinib to AKI rats significantly increased the area under the plasma concentration-time curve from time 0 to infinity (AUC) compared with control (CON) rats, an increase attributed to the decelerated non-renal clearance (CL NR ) and renal clearance (CL R ) of tofacitinib. Administration of LGN to AKI rats, however, protected kidneys from severe impairment, restoring the pharmacokinetic parameters (AUC, CL NR , and CL R ) of tofacitinib to those observed in untreated CON rats, with partial recovery of kidney function, as evidenced by an increase in creatinine clearance (CL CR ). Possible interactions between drugs and natural components should be considered, especially when co-administering both a drug and a natural extract containing LGN or iridoid glycosides to patients with kidney injury.