1q7g
Homoserine Dehydrogenase in complex with suicide inhibitor complex NAD-5-hydroxy-4-OxonorvalineHomoserine Dehydrogenase in complex with suicide inhibitor complex NAD-5-hydroxy-4-Oxonorvaline
Structural highlights
FunctionEvolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe 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. 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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