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October 1, 1990Biochemistry

Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate

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Authors

JDJay F. DaviesPfizer (United States)TDTavner J. DelcampJohnson & Johnson (United States)NPNeal J. PrendergastDuke University

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Implication

Crystallographic analysis reveals structural mechanisms of folate and inhibitor binding in human dihydrofolate reductase, suggesting an optimized transition-state geometry for hydride transfer.

Key Points

To resolve the high-resolution crystal structures of human dihydrofolate reductase complexed with folate and 5-deazafolate to characterize substrate and inhibitor binding mechanisms.
Determined 2.3-Å crystal structures of recombinant human dihydrofolate reductase (EC 1.5.1.3) complexed individually with folate and the inhibitor 5-deazafolate.
Modeled a transition-state complex for folate reduction by superimposing human DHFR–5-deazafolate with chicken liver DHFR–NADPH.
5-deazafolate binds with protonation at N8, inducing a peptide plane rotation between I7 and V8 to form a hydrogen bond with the I7 carbonyl backbone, resulting in higher affinity than unprotonated folate.
Structural superposition revealed a 1-Å overlap between the pteridine ring of folate and the dihydronicotinamide ring of NADPH, creating a sub van der Waals separation optimal for hydride transfer.

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Davies et al. (1990) studied this question.

synapsesocial.com/papers/6a8948cba4df84145ecafded https://doi.org/10.1021/bi00492a021

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Implication

Crystallographic analysis reveals structural mechanisms of folate and inhibitor binding in human dihydrofolate reductase, suggesting an optimized transition-state geometry for hydride transfer.

Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate

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Implication

Key Points

Cite This Study

Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate

Discussion

Member takes

Implication

Key Points

Cite This Study

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