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Inhibiting bacterial transglycosylas...

Ritter, Thomas Kurt.

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Inhibiting bacterial transglycosylases: From small molecules to a library of vancomycin analogs.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Inhibiting bacterial transglycosylases: From small molecules to a library of vancomycin analogs./
Author:	Ritter, Thomas Kurt.
Description:	384 p.
Notes:	Source: Dissertation Abstracts International, Volume: 64-02, Section: B, page: 0721.
Contained By:	Dissertation Abstracts International64-02B.
Subject:	Chemistry, Organic. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3081339

Inhibiting bacterial transglycosylases: From small molecules to a library of vancomycin analogs.
Ritter, Thomas Kurt.

Inhibiting bacterial transglycosylases: From small molecules to a library of vancomycin analogs. - 384 p.

Source: Dissertation Abstracts International, Volume: 64-02, Section: B, page: 0721.

Thesis (Ph.D.)--The Scripps Research Institute, 2003.

The active site of the <italic>E. coli</italic> enzyme dihydrofolate reductase (DHFR) is surrounded by several flexible loops that are involved in ligand binding and catalysis. This study seeks to understand how molecular motion in DHFR correlates with the ligand state and catalytic competency of the enzyme. To achieve this goal, a range of isotopic labeling strategies and nuclear magnetic resonance relaxation techniques were used to probe DHFR dynamics at backbone amides and side-chain imino and methyl sites on the picosecond/nanosecond and microsecond/millisecond time scales. The wild-type ternary complex with folate and NADP<super>+</super>, which assumes a “closed” active site loop conformation, was studied to explore the effects of ligand binding and loop conformation on protein dynamics. The mutant protein G121V in complex with folate was studied to examine the effects on dynamics of a flexible loop mutation that dramatically affects enzyme catalysis. In both studies, the folate-bound wild-type enzyme, which assumes an “occluded” active site loop conformation, served as a comparator. Backbone amide and side-chain imino dynamics were probed by <super>15</super>N nuclear relaxation. Side-chain methyl dynamics on the picosecond/nanosecond time scale were probed by deuterium relaxation and on the microsecond/millisecond time scale by <super>13</super>C relaxation dispersion. The deuterium relaxation studies indicate a loss of side-chain flexibility in the active site loops on fast time scales in the ternary folate:NADP<super>+</super> complex, consistent with backbone dynamics studies. However, relaxation dispersion measurements reveal significant microsecond/millisecond time scale side-chain motion that is consistent with a closed-to-occluded active site loop equilibrium occurring at physiologically relevant rates. In studies of the G121V mutant dynamics, motion at the site of the mutation, as well as in a loop that lies directly over the active site, is diminished. These results suggest a strong correlation between flexibility and catalysis.Subjects--Topical Terms:

516206
Chemistry, Organic.

Inhibiting bacterial transglycosylases: From small molecules to a library of vancomycin analogs.
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245 1 0 $a Inhibiting bacterial transglycosylases: From small molecules to a library of vancomycin analogs.
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500 $a Source: Dissertation Abstracts International, Volume: 64-02, Section: B, page: 0721.
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520 $a The active site of the <italic>E. coli</italic> enzyme dihydrofolate reductase (DHFR) is surrounded by several flexible loops that are involved in ligand binding and catalysis. This study seeks to understand how molecular motion in DHFR correlates with the ligand state and catalytic competency of the enzyme. To achieve this goal, a range of isotopic labeling strategies and nuclear magnetic resonance relaxation techniques were used to probe DHFR dynamics at backbone amides and side-chain imino and methyl sites on the picosecond/nanosecond and microsecond/millisecond time scales. The wild-type ternary complex with folate and NADP<super>+</super>, which assumes a “closed” active site loop conformation, was studied to explore the effects of ligand binding and loop conformation on protein dynamics. The mutant protein G121V in complex with folate was studied to examine the effects on dynamics of a flexible loop mutation that dramatically affects enzyme catalysis. In both studies, the folate-bound wild-type enzyme, which assumes an “occluded” active site loop conformation, served as a comparator. Backbone amide and side-chain imino dynamics were probed by <super>15</super>N nuclear relaxation. Side-chain methyl dynamics on the picosecond/nanosecond time scale were probed by deuterium relaxation and on the microsecond/millisecond time scale by <super>13</super>C relaxation dispersion. The deuterium relaxation studies indicate a loss of side-chain flexibility in the active site loops on fast time scales in the ternary folate:NADP<super>+</super> complex, consistent with backbone dynamics studies. However, relaxation dispersion measurements reveal significant microsecond/millisecond time scale side-chain motion that is consistent with a closed-to-occluded active site loop equilibrium occurring at physiologically relevant rates. In studies of the G121V mutant dynamics, motion at the site of the mutation, as well as in a loop that lies directly over the active site, is diminished. These results suggest a strong correlation between flexibility and catalysis.
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