ArticleBiochemistry2010
Nuclear magnetic resonance study of the role of M42 in the solution dynamics of Escherichia coli dihydrofolate reductase.
Article in Biochemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 32 citations in OpenAlex.
- High throughput mutational scanning of a protein via alchemistry on a high-performance computing resource.bioRxiv : the preprint server for biology · 2024Article
- Allosteric regulatory control in dihydrofolate reductase is revealed by dynamic asymmetry.Protein science : a publication of the Protein Society · 2023Article
- DHFR Mutants Modulate Their Synchronized Dynamics with the Substrate by Shifting Hydrogen Bond Occupancies.Journal of chemical information and modeling · 2022Article
- Concurrent Identification and Characterization of Protein Structure and Continuous Internal Dynamics with REDCRAFT.Frontiers in molecular biosciences · 2022Article
- Effects of Distal Mutations on Ligand-Binding Affinity inACS omega · 2021Article
- Distal Regions Regulate Dihydrofolate Reductase-Ligand Interactions.Methods in molecular biology (Clifton, N.J.) · 2021Review
- Inter-Active Site Communication Mediated by the Dimer Interface β-Sheet in the Half-the-Sites Enzyme, Thymidylate Synthase.Biochemistry · 2019Article
- Chemical space of Escherichia coli dihydrofolate reductase inhibitors: New approaches for discovering novel drugs for old bugs.Medicinal research reviews · 2019Review
- High-pressure protein crystal structure analysis of Escherichia coli dihydrofolate reductase complexed with folate and NADPActa crystallographica. Section D, Structural biology · 2018Article
- Engineered control of enzyme structural dynamics and function.Protein science : a publication of the Protein Society · 2018Review
- Ligand-Dependent Conformational Dynamics of Dihydrofolate Reductase.Biochemistry · 2016Article
- Enzymatic Kinetic Isotope Effects from Path-Integral Free Energy Perturbation Theory.Methods in enzymology · 2016Article
- Connecting protein conformational dynamics with catalytic function as illustrated in dihydrofolate reductase.Biochemistry · 2013Article
- The dark energy of proteins comes to light: conformational entropy and its role in protein function revealed by NMR relaxation.Current opinion in structural biology · 2013Review
- In vitro phosphorylation of the focal adhesion targeting domain of focal adhesion kinase by Src kinase.Biochemistry · 2012Article
- Structure and dynamics of the G121V dihydrofolate reductase mutant: lessons from a transition-state inhibitor complex.PloS one · 2012Article
- Dynamically committed, uncommitted, and quenched states encoded in protein kinase A revealed by NMR spectroscopy.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
- Coupled motions in enzyme catalysis.Current opinion in chemical biology · 2010Review
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.