7CIN

Crystal structure of the extended-spectrum class C beta-lactamase AmpC BER with the ordered R2 loop

Summary for 7CIN

• Entry DOI: 10.2210/pdb7cin/pdb
• Related: 5gzw 5joc
• Descriptor: Beta-lactamase, SULFATE ION (3 entities in total)
• Functional Keywords: class c beta-lactamase, wild-type ampc ber, two amino acid insertion in the r2 loop, ordered r2 loop, hydrolase
• Biological source: Escherichia coli K-12
• Total number of polymer chains: 2
• Total formula weight: 81400.25

Authors

Jeong, B.G.,Cha, S.S. (deposition date: 2020-07-07, release date: 2021-05-19, Last modification date: 2023-11-29)

Primary citation

Jeong, B.G.,Na, J.H.,Bae, D.W.,Park, S.B.,Lee, H.S.,Cha, S.S.
Crystal structure of AmpC BER and molecular docking lead to the discovery of broad inhibition activities of halisulfates against beta-lactamases.
Comput Struct Biotechnol J, 19:145-152, 2021

PubMed Abstract: AmpC BER is an extended-spectrum (ES) class C β-lactamase with a two-amino-acid insertion in the 10 helix region located at the boundary of the active site compared with its narrow spectrum progenitor. The crystal structure of the wild-type AmpC BER revealed that the insertion widens the active site by restructuring the flexible 10 helix region, which is the structural basis for its ES activity. Besides, two sulfates originated from the crystallization solution were observed in the active site. The presence of sulfate-binding subsites, together with the recognition of ring-structured chemical scaffolds by AmpC BER, led us to perform molecular docking experiments with halisulfates, natural products isolated from marine sponge. Inspired by the snug fit of halisulfates within the active site, we demonstrated that halisulfate 3 and 5 significantly inhibit ES class C β-lactamases. Especially, halisulfate 5 is comparable to avibactam in terms of inhibition efficiency; it inhibits the nitrocefin-hydrolyzing activity of AmpC BER with a value of 5.87 μM in a competitive manner. Furthermore, halisulfate 5 displayed moderate and weak inhibition activities against class A and class B/D enzymes, respectively. The treatment of β-lactamase inhibitors (BLIs) in combination with β-lactam antibiotics is a working strategy to cope with infections by pathogens producing ES β-lactamases. Considering the emergence and dissemination of enzymes insensitive to clinically-used BLIs, the broad inhibition spectrum and structural difference of halisulfates would be used to develop novel BLIs that can escape the bacterial resistance mechanism mediated by β-lactamases.

PubMed: 33425247
DOI: 10.1016/j.csbj.2020.12.015

Experimental method

X-RAY DIFFRACTION (1.79006366468 Å)