1Q7G

Homoserine Dehydrogenase in complex with suicide inhibitor complex NAD-5-hydroxy-4-Oxonorvaline

1Q7G の概要

• エントリーDOI: 10.2210/pdb1q7g/pdb
• 分子名称: Homoserine dehydrogenase, SODIUM ION, NICOTINAMIDE-ADENINE-DINUCLEOTIDE-5-HYDROXY-4-OXONORVALINE, ... (4 entities in total)
• 機能のキーワード: oxidoreductase
• 由来する生物種: Saccharomyces cerevisiae (baker's yeast)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 77945.45

構造登録者

Jacques, S.L.,Mirza, I.A.,Ejim, L.,Koteva, K.,Hughes, D.W.,Green, K.,Kinach, R.,Honek, J.F.,Lai, H.K.,Berghuis, A.M.,Wright, G.D. (登録日: 2003-08-18, 公開日: 2003-10-21, 最終更新日: 2023-08-16)

主引用文献

Jacques, S.L.,Mirza, I.A.,Ejim, L.,Koteva, K.,Hughes, D.W.,Green, K.,Kinach, R.,Honek, J.F.,Lai, H.K.,Berghuis, A.M.,Wright, G.D.
Enzyme assisted suicide: Molecular basis for the antifungal activity of 5-hydroxy-4-oxonorvaline by potent inhibition of homoserine dehydrogenase
Chem.Biol., 10:989-995, 2003

PubMed Abstract: The structure of the antifungal drug 5-hydroxy-4-oxonorvaline (HON) in complex with its target homoserine dehydrogenase (HSD) has been determined by X-ray diffraction to 2.6 A resolution. HON shows potent in vitro and in vivo activity against various fungal pathogens despite its weak (2 mM) affinity for HSD in the steady state. The structure together with structure-activity relationship studies, mass spectrometry experiments, and spectroscopic data reveals that the molecular mechanism of antifungal action conferred by HON involves enzyme-dependent formation of a covalent adduct between C4 of the nicotinamide ring of NAD(+) and C5 of HON. Furthermore, novel interactions are involved in stabilizing the (HON*NAD)-adduct, which are not observed in the enzyme's ternary complex structure. These findings clarify the apparent paradox of the potent antifungal actions of HON given its weak steady-state inhibition characteristics.

PubMed: 14583265
DOI: 10.1016/j.chembiol.2003.09.015

実験手法

X-RAY DIFFRACTION (2.6 Å)