6O55

Crystal Structure of N5-carboxyaminoimidazole ribonucleotide mutase (PurE) from Legionella pneumophila

Summary for 6O55

• Entry DOI: 10.2210/pdb6o55/pdb
• Descriptor: N5-carboxyaminoimidazole ribonucleotide mutase, 1,2-ETHANEDIOL, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: ssgcid, mutase, carboxylase, phosphorobosylaminoimidazole carboxylase, structural genomics, seattle structural genomics center for infectious disease, isomerase
• Biological source: Legionella pneumophila subsp. pneumophila (strain Philadelphia 1 / ATCC 33152 / DSM 7513)
• Total number of polymer chains: 4
• Total formula weight: 75018.15

Authors

Seattle Structural Genomics Center for Infectious Disease,Seattle Structural Genomics Center for Infectious Disease (SSGCID) (deposition date: 2019-03-01, release date: 2019-03-13, Last modification date: 2024-05-29)

Primary citation

Belfon, K.K.J.,Sharma, N.,Zigweid, R.,Bolejack, M.,Davies, D.,Edwards, T.E.,Myler, P.J.,French, J.B.
Structure-Guided Discovery of N 5 -CAIR Mutase Inhibitors.
Biochemistry, 62:2587-2596, 2023

PubMed Abstract: Because purine nucleotides are essential for all life, differences between how microbes and humans metabolize purines can be exploited for the development of antimicrobial therapies. While humans biosynthesize purine nucleotides in a 10-step pathway, most microbes utilize an additional 11th enzymatic activity. The human enzyme, aminoimidazole ribonucleotide (AIR) carboxylase generates the product 4-carboxy-5-aminoimidazole ribonucleotide (CAIR) directly. Most microbes, however, require two separate enzymes, a synthetase (PurK) and a mutase (PurE), and proceed through the intermediate, N-CAIR. Toward the development of therapeutics that target these differences, we have solved crystal structures of the N-CAIR mutase of the human pathogens (LpPurE) and (BcPurE) and used a structure-guided approach to identify inhibitors. Analysis of the structures reveals a highly conserved fold and active site architecture. Using this data, and three additional structures of PurE enzymes, we screened a library of FDA-approved compounds and identified a set of 25 candidates for further analysis. Among these, we identified several new PurE inhibitors with micromolar IC values. Several of these compounds, including the α-blocker Alfuzosin, inhibit the microbial PurE enzymes much more effectively than the human homologue. These structures and the newly described PurE inhibitors are valuable tools to aid in further studies of this enzyme and provide a foundation for the development of compounds that target differences between human and microbial purine metabolism.

PubMed: 37552766
DOI: 10.1021/acs.biochem.2c00705

Experimental method

X-RAY DIFFRACTION (1.7 Å)