Non-catalytic-Region Mutations Conferring Transition of Class A beta-Lactamases Into ESBLs
- Authors
- Cao, Thinh-Phat; Yi, Hyojeong; Dhanasingh, Immanuel; Ghosh, Suparna; Choi, Jin Myung; Lee, Kun Ho; Ryu, Seol; Kim, Heenam Stanley; Lee, Sung Haeng
- Issue Date
- 27-11월-2020
- Publisher
- FRONTIERS MEDIA SA
- Keywords
- extended-spectrum & #946; -lactamase; non-catalytic-region ESBL; ceftazidime; antibiotic resistance; X-ray crystallography
- Citation
- FRONTIERS IN MOLECULAR BIOSCIENCES, v.7
- Indexed
- SCIE
SCOPUS
- Journal Title
- FRONTIERS IN MOLECULAR BIOSCIENCES
- Volume
- 7
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/51444
- DOI
- 10.3389/fmolb.2020.598998
- ISSN
- 2296-889X
- Abstract
- Despite class A ESBLs carrying substitutions outside catalytic regions, such as Cys69Tyr or Asn136Asp, have emerged as new clinical threats, the molecular mechanisms underlying their acquired antibiotics-hydrolytic activity remains unclear. We discovered that this non-catalytic-region (NCR) mutations induce significant dislocation of beta 3-beta 4 strands, conformational changes in critical residues associated with ligand binding to the lid domain, dynamic fluctuation of omega-loop and beta 3-beta 4 elements. Such structural changes increase catalytic regions' flexibility, enlarge active site, and thereby accommodate third-generation cephalosporin antibiotics, ceftazidime (CAZ). Notably, the electrostatic property around the oxyanion hole of Cys69Tyr ESBL is significantly changed, resulting in possible additional stabilization of the acyl-enzyme intermediate. Interestingly, the NCR mutations are as effective for antibiotic resistance by altering the structure and dynamics in regions mediating substrate recognition and binding as single amino-acid substitutions in the catalytic region of the canonical ESBLs. We believe that our findings are crucial in developing successful therapeutic strategies against diverse class A ESBLs, including the new NCR-ESBLs.
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Collections - College of Health Sciences > School of Biosystems and Biomedical Sciences > 1. Journal Articles
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