ArticleBiochemistry2007
Crystal structure of a type II dihydrofolate reductase catalytic ternary complex.
Article in Biochemistry, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- From Binding to Catalysis: Emergence of a Rudimentary Enzyme Conferring Intrinsic Antibiotic Resistance.Molecular biology and evolution · 2025Article
- Crystal structure of the plasmid-encoded R67 dihydrofolate reductase complexed with Congo red an amyloid binding dye.Scientific reports · 2025Article
- Deep mutational scanning of Pneumocystis jirovecii dihydrofolate reductase reveals allosteric mechanism of resistance to an antifolate.PLoS genetics · 2024Article
- A conserved SH3-like fold in diverse putative proteins tetramerizes into an oxidoreductase providing an antimicrobial resistance phenotype.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Article
- Epistasis between promoter activity and coding mutations shapes gene evolvability.Science advances · 2023Article
- Discovery of Highly Trimethoprim-Resistant DfrB Dihydrofolate Reductases in Diverse Environmental Settings Suggests an Evolutionary Advantage Unrelated to Antibiotic Resistance.Antibiotics (Basel, Switzerland) · 2022Article
- Computational Development of Inhibitors of Plasmid-Borne Bacterial Dihydrofolate Reductase.Antibiotics (Basel, Switzerland) · 2022Article
- The Bacterial Genomic Context of Highly Trimethoprim-Resistant DfrB Dihydrofolate Reductases Highlights an Emerging Threat to Public Health.Antibiotics (Basel, Switzerland) · 2021Article
- Temperature-Dependent Kinetic Isotope Effects in R67 Dihydrofolate Reductase from Path-Integral Simulations.The journal of physical chemistry. B · 2021Article
- Dual-Target Inhibitors of the Folate Pathway Inhibit Intrinsically Trimethoprim-Resistant DfrB Dihydrofolate Reductases.ACS medicinal chemistry letters · 2020Article
- Article
- Crowders Steal Dihydrofolate Reductase Ligands through Quinary Interactions.Biochemistry · 2019Article
- Small Angle Neutron Scattering Studies of R67 Dihydrofolate Reductase, a Tetrameric Protein with Intrinsically Disordered N-Termini.Biochemistry · 2017Article
- Classification of ligand molecules in PDB with graph match-based structural superposition.Journal of structural and functional genomics · 2016Article
- Aspects of Weak Interactions between Folate and Glycine Betaine.Biochemistry · 2016Article
- A Small Protein Associated with Fungal Energy Metabolism Affects the Virulence of Cryptococcus neoformans in Mammals.PLoS pathogens · 2016Article
- Tales of Dihydrofolate Binding to R67 Dihydrofolate Reductase.Biochemistry · 2016Article
- Asymmetric mutations in the tetrameric R67 dihydrofolate reductase reveal high tolerance to active-site substitutions.Protein science : a publication of the Protein Society · 2015Article
- Thermodynamics and solvent linkage of macromolecule-ligand interactions.Methods (San Diego, Calif.) · 2015Review
- Structure of the hypothetical DUF1811-family protein GK0453 from Geobacillus kaustophilus HTA426.Acta crystallographica. Section F, Structural biology and crystallization communications · 2013Article
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5 authors.
Funding
Abstract
Type II dihydrofolate reductase (DHFR) is a plasmid-encoded enzyme that confers resistance to bacterial DHFR-targeted antifolate drugs. It forms a symmetric homotetramer with a central pore which functions as the active site. Its unusual structure, which results in a promiscuous binding surface that accommodates either the dihydrofolate (DHF) substrate or the NADPH cofactor, has constituted a significant limitation to efforts to understand its substrate specificity and reaction mechanism. We describe here the first structure of a ternary R67 DHFR.DHF.NADP+ catalytic complex, resolved to 1.26 A. This structure provides the first clear picture of how this enzyme, which lacks the active site carboxyl residue that is ubiquitous in Type I DHFRs, is able to function. In the catalytic complex, the polar backbone atoms of two symmetry-related I68 residues provide recognition motifs that interact with the carboxamide on the nicotinamide ring, and the N3-O4 amide function on the pteridine ring. This set of interactions orients the aromatic rings of substrate and cofactor in a relative endo geometry in which the reactive centers are held in close proximity. Additionally, a central, hydrogen-bonded network consisting of two pairs of Y69-Q67-Q67'-Y69' residues provides an unusually tight interface, which appears to serve as a "molecular clamp" holding the substrates in place in an orientation conducive to hydride transfer. In addition to providing the first clear insight regarding how this extremely unusual enzyme is able to function, the structure of the ternary complex provides general insights into how a mutationally challenged enzyme, i.e., an enzyme whose evolution is restricted to four-residues-at-a-time active site mutations, overcomes this fundamental limitation.
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