Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
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Journal
IF	>30 >20 >10 >5 all

Title	Structures of trehalose-6-phosphate synthase, Tps1, from the fungal pathogen : a target for novel antifungals.
Journal, issue, pages	bioRxiv, Year 2023
Publish date	Mar 14, 2023
Authors	Erica J Washington / Ye Zhou / Allen L Hsu / Matthew Petrovich / Mario J Borgnia / Alberto Bartesaghi / Richard G Brennan /
PubMed Abstract	Invasive fungal diseases are a major threat to human health, resulting in more than 1.5 million deaths worldwide each year. Yet the arsenal of antifungal therapeutics remains limited and is in dire ...Invasive fungal diseases are a major threat to human health, resulting in more than 1.5 million deaths worldwide each year. Yet the arsenal of antifungal therapeutics remains limited and is in dire need of novel drugs that target additional fungal-specific biosynthetic pathways. One such pathway involves the biosynthesis of trehalose. Trehalose is a non-reducing disaccharide composed of two molecules of glucose that is required for pathogenic fungi, including and , to survive in their human hosts. Trehalose biosynthesis is a two-step process in fungal pathogens. Trehalose-6-phosphate synthase (Tps1) converts UDP-glucose and glucose-6-phosphate to trehalose-6-phosphate (T6P). Subsequently, trehalose-6-phosphate phosphatase (Tps2) converts T6P to trehalose. The trehalose biosynthesis pathway has been identified as a top candidate for novel antifungal development based on quality, occurrence, specificity, and assay development. However, there are currently no known antifungal agents that target this pathway. As initial steps to develop Tps1 from (CnTps1) as a drug target, we report the structures of full-length CnTps1 and CnTps1 in complex with uridine diphosphate (UDP) and glucose-6-phosphate (G6P). Both CnTps1 structures are tetramers and display D2 (222) molecular symmetry. Comparison of these two structures reveals significant movement towards the catalytic pocket by the N-terminus upon ligand binding and identifies key residues required for substrate-binding, which are conserved amongst other Tps1 enzymes, as well as residues that stabilize the tetramer. Intriguingly, an intrinsically disordered domain (IDD), encompassing residues M209 to I300, which is conserved amongst Cryptococcal species and closely related Basidiomycetes, extends from each subunit of the tetramer into the "solvent" but is not visible in the density maps. Although, activity assays revealed that the highly conserved IDD is not required for catalysis , we hypothesize that the IDD is required for Tps1-dependent thermotolerance and osmotic stress survival. Characterization of the substrate specificity of CnTps1 revealed that UDP-galactose, an epimer of UDP-glucose, is a very poor substrate and inhibitor of the enzyme and highlights the exquisite substrate specificity of Tps1. , these studies expand our knowledge of trehalose biosynthesis in and highlight the potential of developing antifungal therapeutics that disrupt the synthesis of this disaccharide or the formation of a functional tetramer and the use of cryo-EM in the structural characterization of CnTps1-ligand/drug complexes.
External links	bioRxiv / PubMed:36993618 / PubMed Central
Methods	EM (single particle)
Resolution	3.2 Å
Structure data	29172 8fhw EMDB-29172, PDB-8fhw: Cryo-EM structure of Cryptococcus neoformans trehalose-6-phosphate synthase homotetramer in complex with uridine diphosphate and glucose-6-phosphate Method: EM (single particle) / Resolution: 3.2 Å
Chemicals	ChemComp-UDP: URIDINE-5'-DIPHOSPHATE / UDPYM / Uridine diphosphate ChemComp-G6P*: 6-O-phosphono-alpha-D-glucopyranose
Source	cryptococcus neoformans var. grubii h99 (fungus)
Keywords	TRANSFERASE / Glycosyltransferase / Complex