7boo
From Proteopedia
Crystal Structure of Core-mannan synthase A (CmsA/Ktr4) from Aspergillus fumigatus, apo form
Structural highlights
Publication Abstract from PubMedFungal cell walls and their biosynthetic enzymes are potential targets for novel antifungal agents. Recently, two mannosyltransferases, namely core-mannan synthases A (CmsA/Ktr4) and B (CmsB/Ktr7), were found to play roles in the core-mannan biosynthesis of fungal-type galactomannan. CmsA/Ktr4 is an alpha-(1-->2)-mannosyltransferase responsible for alpha-(1-->2)-mannan biosynthesis in fungal-type galactomannan, which covers the cell surface of Aspergillus fumigatus Strains with disrupted cmsA/ktr4 have been shown to exhibit strongly suppressed hyphal elongation and conidiation alongside reduced virulence in a mouse model of invasive aspergillosis, indicating that CmsA/Ktr4 is a potential novel antifungal candidate. In this study we present the 3-D structures of the soluble catalytic domain of CmsA/Ktr4, as determined by X-ray crystallography at a resolution of 1.95A, as well as the enzyme and Mn(2+)/GDP complex to 1.90A resolution. The CmsA/Ktr4 protein not only contains a highly conserved binding pocket for the donor substrate, GDP-mannose, but also has a unique broad cleft structure formed by its N- and C-terminal regions and is expected to recognize the acceptor substrate, a mannan chain. Based on these crystal structures, we also present a 3-D structural model of the enzyme-substrate complex generated using docking and molecular dynamics simulations with alpha-Man-(1-->6)-alpha-Man-(1-->2)-alpha-Man-OMe as the model structure for the acceptor substrate. This predicted enzyme-substrate complex structure is also supported by findings from single amino acid substitution CmsA/Ktr4 mutants expressed in DeltacmsA/ktr4 A fumigatus cells. Taken together, these results provide basic information for developing specific alpha-mannan biosynthesis inhibitors for use as pharmaceuticals and/or pesticides. Structural basis for the core-mannan biosynthesis of cell wall fungal-type galactomannan in Aspergillus fumigatus.,Hira D, Onoue T, Oka T J Biol Chem. 2020 Sep 1. pii: RA120.013742. doi: 10.1074/jbc.RA120.013742. PMID:32873705[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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