1q7g
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Homoserine Dehydrogenase in complex with suicide inhibitor complex NAD-5-hydroxy-4-Oxonorvaline
OverviewOverview
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.
About this StructureAbout this Structure
1Q7G is a Single protein structure of sequence from Saccharomyces cerevisiae with NA and NHO as ligands. Active as Homoserine dehydrogenase, with EC number 1.1.1.3 Full crystallographic information is available from OCA.
ReferenceReference
Enzyme-assisted suicide: molecular basis for the antifungal activity of 5-hydroxy-4-oxonorvaline by potent inhibition of homoserine dehydrogenase., Jacques SL, Mirza IA, Ejim L, Koteva K, Hughes DW, Green K, Kinach R, Honek JF, Lai HK, Berghuis AM, Wright GD, Chem Biol. 2003 Oct;10(10):989-95. PMID:14583265
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