8DB7

Adenosine/guanosine nucleoside hydrolase bound to a fragment inhibitor

Summary for 8DB7

• Entry DOI: 10.2210/pdb8db7/pdb
• Descriptor: Inosine-uridine preferring nucleoside hydrolase family protein, GLYCEROL, N-(4-fluorophenyl)-4,5-dihydro-1H-imidazol-2-amine, ... (5 entities in total)
• Functional Keywords: nucleoside, hydrolase, adenosine, guanosine, parasitic, inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Trichomonas vaginalis
• Total number of polymer chains: 4
• Total formula weight: 134971.61

Authors

Muellers, S.N.,Allen, K.N.,Stockman, B.J. (deposition date: 2022-06-14, release date: 2022-09-07, Last modification date: 2024-04-03)

Primary citation

Muellers, S.N.,Nyitray, M.M.,Reynarowych, N.,Saljanin, E.,Benzie, A.L.,Schoenfeld, A.R.,Stockman, B.J.,Allen, K.N.
Structure-Guided Insight into the Specificity and Mechanism of a Parasitic Nucleoside Hydrolase.
Biochemistry, 61:1853-1861, 2022

PubMed Abstract: is the causative parasitic protozoan of the disease trichomoniasis, the most prevalent, nonviral sexually transmitted disease in the world. is a parasite that scavenges nucleosides from the host organism via catalysis by nucleoside hydrolase (NH) enzymes to yield purine and pyrimidine bases. One of the four NH enzymes identified within the genome of displays unique specificity toward purine nucleosides, adenosine and guanosine, but not inosine, and atypically shares greater sequence similarity to the pyrimidine hydrolases. Bioinformatic analysis of this enzyme, adenosine/guanosine-preferring nucleoside ribohydrolase (AGNH), was incapable of identifying the residues responsible for this uncommon specificity, highlighting the need for structural information. Here, we report the X-ray crystal structures of , unliganded AGNH and three additional structures of the enzyme bound to fragment and small-molecule inhibitors. Taken together, these structures facilitated the identification of residue Asp231, which engages in substrate interactions in the absence of those residues that typically support the canonical purine-specific tryptophan-stacking specificity motif. An altered substrate-binding pose is mirrored by repositioning within the protein scaffold of the His80 general acid/base catalyst. The newly defined structure-determined sequence markers allowed the assignment of additional NH orthologs, which are proposed to exhibit the same specificity for adenosine and guanosine alone and further delineate specificity classes for these enzymes.

PubMed: 35994320
DOI: 10.1021/acs.biochem.2c00361

Experimental method

X-RAY DIFFRACTION (2.33 Å)