7ZCY

Sporosarcina pasteurii urease (SPU) co-crystallized in the presence of an Ebselen-derivative and bound to Se atoms

Summary for 7ZCY

• Entry DOI: 10.2210/pdb7zcy/pdb
• Descriptor: Urease subunit gamma, Urease subunit beta, Urease subunit alpha, ... (10 entities in total)
• Functional Keywords: urease, nickel, ebselen, selenium, hydrolase
• Biological source: Sporosarcina pasteurii; More
• Total number of polymer chains: 3
• Total formula weight: 88870.41

Authors

Mazzei, L.,Ciurli, S.,Cianci, M. (deposition date: 2022-03-29, release date: 2023-04-19, Last modification date: 2024-02-07)

Primary citation

Macegoniuk, K.,Tabor, W.,Mazzei, L.,Cianci, M.,Giurg, M.,Olech, K.,Burda-Grabowska, M.,Kaleta, R.,Grabowiecka, A.,Mucha, A.,Ciurli, S.,Berlicki, L.
Optimized Ebselen-Based Inhibitors of Bacterial Ureases with Nontypical Mode of Action.
J.Med.Chem., 66:2054-2063, 2023

PubMed Abstract: Screening of 25 analogs of Ebselen, diversified at the N-aromatic residue, led to the identification of the most potent inhibitors of urease reported to date. The presence of a dihalogenated phenyl ring caused exceptional activity of these 1,2-benzisoselenazol-3(2)-ones, with value in a low picomolar range (<20 pM). The affinity was attributed to the increased π-π and π-cation interactions of the dihalogenated phenyl ring with αHis323 and αArg339 during the initial step of binding. Complementary biological studies with selected compounds on the inhibition of ureolysis in whole cells showed a very good potency (IC < 25 nM in phosphate-buffered saline (PBS) buffer and IC < 50 nM in a urine model) for monosubstituted N-phenyl derivatives. The crystal structure of urease inhibited by one of the most active analogs revealed the recurrent selenation of the Cys322 thiolate, yielding an unprecedented Cys322-S-Se-Se chemical moiety.

PubMed: 36661843
DOI: 10.1021/acs.jmedchem.2c01799

Experimental method

X-RAY DIFFRACTION (1.54 Å)