8E4F

Crystal structure of dihydrofolate reductase (DHFR) from the filarial nematode W. bancrofti in complex with NADPH and folate

8E4F の概要

• エントリーDOI: 10.2210/pdb8e4f/pdb
• 分子名称: Dihydrofolate reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, FOLIC ACID, ... (5 entities in total)
• 機能のキーワード: reductase, oxidoreductase
• 由来する生物種: Wuchereria bancrofti
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 23635.58

構造登録者

Lange, K.,Frey, K.M.,Goodey, N.M. (登録日: 2022-08-18, 公開日: 2023-05-10, 最終更新日: 2023-10-25)

主引用文献

Lange, K.,Frey, K.M.,Eck, T.,Janson, C.A.,Gubler, U.,Goodey, N.M.
Crystal structure of dihydrofolate reductase from the filarial nematode W. bancrofti in complex with NADPH and folate.
Plos Negl Trop Dis, 17:e0011303-e0011303, 2023

PubMed Abstract: Lymphatic filariasis is a debilitating illness with an estimated 50 million cases as of 2018. The majority of cases are caused by the parasitic worm W. bancrofti and additional cases by the worms B. malayi and B. timori. Dihydrofolate reductase (DHFR) is an established target in the treatment of cancer, bacterial, and protozoal infections and may be a potential target for drugs targeting parasitic worm infections, including filariasis. Recent studies have shown that known antifolate compounds, including methotrexate, inhibit the activity of W. bancrofti DHFR (WbDHFR). However, the absence of structural information for filarial DHFRs has limited the study of more in-depth structure-function relationships. We report the structure of WbDHFR complexed with NADPH and folate using X-ray diffraction data measured to 2.47 Å resolution. The structure of WbDHFR reveals the usual DHFR fold and is currently only the second nematode DHFR structure in the Protein Data Bank. The equilibrium dissociation constants for NADPH (90 ± 29 nM) and folate (23 ± 4 nM) were determined by equilibrium titrations. The interactions of known antifolates with WbDHFR were analyzed using molecular docking programs and molecular dynamics simulations. Antifolates with a hydrophobic core and extended linker formed favorable interactions with WbDHFR. These combined data should now facilitate the rational design of filarial DHFR inhibitors, which in turn can be used to determine whether DHFR is a viable drug target for filariasis and whether existing antifolates may be repurposed for its treatment.

PubMed: 37104530
DOI: 10.1371/journal.pntd.0011303

実験手法

X-RAY DIFFRACTION (2.47 Å)