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• W2074364042 startingPage "1606" @default.
• W2074364042 abstract "It is widely recognized that key positions throughout a protein's structure contribute unequally to function. In light of recent studies that suggest protein dynamics are required for function, a number of these residues may serve to promote motions required for ligand binding and catalysis. In this nuclear magnetic resonance (NMR) study, the conformational dynamics of the dihydrofolate reductase (DHFR) mutant M42W, in the presence of methotrexate and NADPH, are characterized and compared to those of the wild-type enzyme. M42 is distal to the active site, yet the M42W substitution regulates catalysis and ligand affinity and is therefore analogous to an allosteric modulator of DHFR function. To gain understanding of how this mutation regulates activity, we employ a pandynamic strategy by measuring conformational fluctuations of backbone amide and side-chain methyl groups on multiple time scales. Changes in pico- to nanosecond dynamics indicate that the mutational effects are propagated throughout a network of interacting residues within DHFR, consistent with a role for M42 as a dynamic communication hub. On the micro- to millisecond time scale, mutation increases the rate of switching in the catalytic core. Mutation also introduces switching in the adenosine binding subdomain that occurs at a higher frequency than in the catalytic core and which correlates with the rate of product release for M42W-DHFR. Finally, a structurally inferred analysis of side-chain dynamics suggests that the M42W mutation dampens motional contributions from nonlocal sources. These data show that the M42W mutation alters the dynamics of DHFR and are consistent with theoretical analysis that suggests this mutation disrupts motion that promotes catalysis." @default.
• W2074364042 created "2016-06-24" @default.
• W2074364042 creator A5010573181 @default.
• W2074364042 creator A5065974767 @default.
• W2074364042 date "2010-02-04" @default.
• W2074364042 modified "2023-10-16" @default.
• W2074364042 title "Nuclear Magnetic Resonance Study of the Role of M42 in the Solution Dynamics of <i>Escherichia coli</i> Dihydrofolate Reductase" @default.
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• W2074364042 doi "https://doi.org/10.1021/bi901798g" @default.
• W2074364042 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2872547" @default.
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