Download MendeleyInteraction of Cephalosporins with Human Serum Albumin: A Structural Study.
Kawai, A., Yamasaki, K., Otagiri, M., Doi, Y.(2024) J Med Chem 67: 14175-14183
- PubMed: 39083648
- DOI: https://doi.org/10.1021/acs.jmedchem.4c00983
- Primary Citation of Related Structures:
8YXA, 8YXB - PubMed Abstract:
Modification of the R1 and R2 side chain structures has been used as the main strategy to expand the spectrum of cephalosporins and impart resistance to hydrolysis by ¦Â-lactamases. These structural modifications also result in a wide range of plasma protein binding, especially with human serum albumin (HSA). Here, we determined the crystal structures of the HSA complexes with two clinically important cephalosporins, ceftriaxone and cefazolin, and evaluated the binding of cephalosporin to HSA by susceptibility testing and competitive binding assay. Ceftriaxone and cefazolin bind to subdomain IB of HSA, and their cephem core structures are recognized by Arg117 of HSA. Tyr161 of HSA changes its rotamer depending on the cephalosporin, resulting in alterations of the cavity shape occupied by the R2 side chain of cephalosporins. These findings provide structural insight into the mechanisms underlying the HSA binding of cephalosporins.
Organizational Affiliation:
Department of Microbiology, Fujita Health University School of Medicine, 1-98, Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan.
