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Structural insights into inhibitor binding to a fungal ortholog of aspartate semialdehyde dehydrogenase
Ist Teil von
Biochemical and biophysical research communications, 2018-09, Vol.503 (4), p.2848-2854
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2018
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
The aspartate pathway, uniquely found in plants and microorganisms, offers novel potential targets for the development of new antimicrobial drugs. Aspartate semialdehyde dehydrogenase (ASADH) catalyzes production of a key intermediate at the first branch point in this pathway. Several fungal ASADH structures have been determined, but the prior crystallization conditions had precluded complex formation with enzyme inhibitors. The first inhibitor-bound and cofactor-bound structures of ASADH from the pathogenic fungi Blastomyces dermatitidis have now been determined, along with a structural and functional comparison to other ASADH family members. The structure of this new ASADH is similar to the other fungal orthologs, but with some critical differences in the orientation of some active site functional groups and in the subunit interface region. The presence of this bound inhibitor reveals the first details about inhibitor binding interactions, and the flexible orientation of its aromatic ring provides helpful insights into the design of potentially more potent and selective antifungal compounds.
•Structure of an inhibitor bound to an essential fungal enzyme.•Effects of cofactor binding on oligomeric assembly.•Structure guided docking of a potent fungal enzyme inhibitor.•Structural comparison to related microbial enzymes.