7MO6

Guanosine Monophosphate Synthase from Aspergillus fumigatus Af293

Summary for 7MO6

• Entry DOI: 10.2210/pdb7mo6/pdb
• Descriptor: GMP synthase [glutamine-hydrolyzing] (2 entities in total)
• Functional Keywords: guanosine monophosphate synthase, purine biosynthesis, ligase
• Biological source: Aspergillus fumigatus Af293
• Total number of polymer chains: 2
• Total formula weight: 119214.45

Authors

Nguyen, S.,Bruning, J.B. (deposition date: 2021-05-01, release date: 2022-02-16, Last modification date: 2023-10-18)

Primary citation

Nguyen, S.,Jovcevski, B.,Pukala, T.L.,Bruning, J.B.
Structural insights into the antifungal drug target guanosine monophosphate synthase from Aspergillus fumigatus.
Acta Crystallogr D Struct Biol, 78:248-259, 2022

PubMed Abstract: Purine biosynthesis is a fundamental cellular process that sustains life by maintaining the intracellular pool of purines for DNA/RNA synthesis and signal transduction. As an integral determinant of fungal survival and virulence, the enzymes in this metabolic pathway have been pursued as potential antifungal targets. Guanosine monophosphate (GMP) synthase has been identified as an attractive target as it is essential for virulence in the clinically prominent fungal pathogens Aspergillus fumigatus, Candida albicans and Cryptococcus neoformans. However, a lack of structural information on GMP synthase has hindered drug-design efforts. Here, the first structure of a GMP synthase of fungal origin, that from A. fumigatus (at 2.3 Å resolution), is presented. Structural analysis of GMP synthase shows a distinct absence of the D1 dimerization domain that is present in the human homologue. Interestingly, A. fumigatus GMP synthase adopts a dimeric state, as determined by native mass spectrometry and gel-filtration chromatography, in contrast to the monomeric human homologue. Analysis of the substrate-binding pockets of A. fumigatus GMP synthase reveals key differences in the ATP- and XMP-binding sites that can be exploited for species-specific inhibitor drug design. Furthermore, the inhibitory activities of the glutamine analogues acivicin (IC = 16.6 ± 2.4 µM) and 6-diazo-5-oxo-L-norleucine (IC = 29.6 ± 5.6 µM) against A. fumigatus GMP synthase are demonstrated. Together, these data provide crucial structural information required for specifically targeting A. fumigatus GMP synthase for future antifungal drug-discovery endeavours.

PubMed: 35102890
DOI: 10.1107/S2059798321012031

Experimental method

X-RAY DIFFRACTION (2.3 Å)