2VXK

Structural comparison between Aspergillus fumigatus and human GNA1

Summary for 2VXK

• Entry DOI: 10.2210/pdb2vxk/pdb
• Related: 2VEZ
• Descriptor: GLUCOSAMINE 6-PHOSPHATE ACETYLTRANSFERASE, 2-acetamido-2-deoxy-6-O-phosphono-alpha-D-glucopyranose, PHOSPHATE ION, ... (5 entities in total)
• Functional Keywords: kinetics, udp-glcnac, transferase, inhibitor design
• Biological source: ASPERGILLUS FUMIGATUS
• Total number of polymer chains: 1
• Total formula weight: 22289.81

Authors

Hurtado-Guerrero, R.,Raimi, O.G.,Min, J.,Zeng, H.,Vallius, L.,Shepherd, S.,Ibrahim, A.F.M.,Wu, H.,Plotnikov, A.N.,van Aalten, D.M.F. (deposition date: 2008-07-05, release date: 2008-07-15, Last modification date: 2024-05-08)

Primary citation

Hurtado-Guerrero, R.,Raimi, O.G.,Min, J.,Zeng, H.,Vallius, L.,Shepherd, S.,Ibrahim, A.F.M.,Wu, H.,Plotnikov, A.N.,Van Aalten, D.M.F.
Structural and Kinetic Differences between Human and Aspergillus Fumigatus D-Glucosamine-6- Phosphate N-Acetyltransferase.
Biochem.J., 415:217-, 2008

PubMed Abstract: Aspergillus fumigatus is the causative agent of aspergillosis, a frequently invasive colonization of the lungs of immunocompromised patients. GNA1 (D-glucosamine-6-phosphate N-acetyltransferase) catalyses the acetylation of GlcN-6P (glucosamine-6-phosphate) to GlcNAc-6P (N-acetylglucosamine-6-phosphate), a key intermediate in the UDP-GlcNAc biosynthetic pathway. Gene disruption of gna1 in yeast and Candida albicans has provided genetic validation of the enzyme as a potential target. An understanding of potential active site differences between the human and A. fumigatus enzymes is required to enable further work aimed at identifying selective inhibitors for the fungal enzyme. In the present study, we describe crystal structures of both human and A. fumigatus GNA1, as well as their kinetic characterization. The structures show significant differences in the sugar-binding site with, in particular, several non-conservative substitutions near the phosphate-binding pocket. Mutagenesis targeting these differences revealed drastic effects on steady-state kinetics, suggesting that the differences could be exploitable with small-molecule inhibitors.

PubMed: 18601654
DOI: 10.1042/BJ20081000

Experimental method

X-RAY DIFFRACTION (1.8 Å)