Correction to Effect of Cofactor Binding and Loop Conformation on Side Chain Methyl Dynamics in Dihydrofolate Reductase

Biochemistry ◽  
2013 ◽  
Vol 52 (13) ◽  
pp. 2383-2383
Author(s):  
Jason R. Schnell ◽  
H. Jane Dyson ◽  
Peter E. Wright
Keyword(s):  
Dihydrofolate Reductase ◽  
Side Chain ◽  
Cofactor Binding ◽  
Methyl Dynamics ◽  
Loop Conformation

scholarly journals Diagnostic chemical shift markers for loop conformation and substrate and cofactor binding in dihydrofolate reductase complexes

2009 ◽  
Vol 12 (10) ◽  
pp. 2230-2238 ◽  
Author(s):  
Michael J. Osborne ◽  
Rani P. Venkitakrishnan ◽  
H. Jane Dyson ◽  
Peter E. Wright
Keyword(s):  
Chemical Shift ◽  
Dihydrofolate Reductase ◽  
Cofactor Binding ◽  
Loop Conformation

scholarly journals Tying up the Loose Ends: A Mathematically Knotted Protein

2021 ◽  
Vol 9 ◽  
Author(s):  
Shang-Te Danny Hsu ◽  
Yun-Tzai Cloud Lee ◽  
Kornelia M. Mikula ◽  
Sofia M. Backlund ◽  
Igor Tascón ◽  
...  
Keyword(s):  
Polymer Chains ◽  
Side Chain ◽  
Denatured State ◽  
Cofactor Binding ◽  
Physico Chemical ◽  
Theoretical Predictions ◽  
Backbone Cyclization ◽  
Knotted Protein ◽  
Chemical Attributes ◽  
Polypeptide Chains

Knots have attracted scientists in mathematics, physics, biology, and engineering. Long flexible thin strings easily knot and tangle as experienced in our daily life. Similarly, long polymer chains inevitably tend to get trapped into knots. Little is known about their formation or function in proteins despite >1,000 knotted proteins identified in nature. However, these protein knots are not mathematical knots with their backbone polypeptide chains because of their open termini, and the presence of a “knot” depends on the algorithm used to create path closure. Furthermore, it is generally not possible to control the topology of the unfolded states of proteins, therefore making it challenging to characterize functional and physicochemical properties of knotting in any polymer. Covalently linking the amino and carboxyl termini of the deeply trefoil-knotted YibK from Pseudomonas aeruginosa allowed us to create the truly backbone knotted protein by enzymatic peptide ligation. Moreover, we produced and investigated backbone cyclized YibK without any knotted structure. Thus, we could directly probe the effect of the backbone knot and the decrease in conformational entropy on protein folding. The backbone cyclization did not perturb the native structure and its cofactor binding affinity, but it substantially increased the thermal stability and reduced the aggregation propensity. The enhanced stability of a backbone knotted YibK could be mainly originated from an increased ruggedness of its free energy landscape and the destabilization of the denatured state by backbone cyclization with little contribution from a knot structure. Despite the heterogeneity in the side-chain compositions, the chemically unfolded cyclized YibK exhibited several macroscopic physico-chemical attributes that agree with theoretical predictions derived from polymer physics.

scholarly journals Crystal Structure of Bacillus anthracis Dihydrofolate Reductase with the Dihydrophthalazine-Based Trimethoprim Derivative RAB1 Provides a Structural Explanation of Potency and Selectivity

2009 ◽  
Vol 53 (7) ◽  
pp. 3065-3073 ◽  
Author(s):  
Christina R. Bourne ◽  
Richard A. Bunce ◽  
Philip C. Bourne ◽  
K. Darrell Berlin ◽  
Esther W. Barrow ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Dihydrofolate Reductase ◽  
Active Site ◽  
Inhibitory Concentration ◽  
Side Chain ◽  
Natural Substrate ◽  
X Ray Diffraction ◽  
Structural Explanation ◽  
X Ray ◽  
Hydrophobic Anchor

ABSTRACT Bacillus anthracis possesses an innate resistance to the antibiotic trimethoprim due to poor binding to dihydrofolate reductase (DHFR); currently, there are no commercial antibacterials that target this enzyme in B. anthracis. We have previously reported a series of dihydrophthalazine-based trimethoprim derivatives that are inhibitors for this target. In the present work, we have synthesized one compound (RAB1) displaying favorable 50% inhibitory concentration (54 nM) and MIC (≤12.8 μg/ml) values. RAB1 was cocrystallized with the B. anthracis DHFR in the space group P212121, and X-ray diffraction data were collected to a 2.3-Å resolution. Binding of RAB1 causes a conformational change of the side chain of Arg58 and Met37 to accommodate the dihydrophthalazine moiety. Unlike the natural substrate or trimethoprim, the dihydrophthalazine group provides a large hydrophobic anchor that embeds within the DHFR active site and accounts for its selective inhibitory activity against B. anthracis.

Sign in / Sign up

Export Citation Format

Share Document