Organism Specific Differences in Binding of Ketoprofen to Serum Albumin
Mateusz P. Czub, Alan J. Stewart, Ivan G. Shabalin, and Wladek Minor [1]
Molecular Tour
Serum albumin (SA) is the most abundant plasma protein and a transporter of hormones, metal ions, and common metabolites, such as fatty acids and sugars, in the blood[2][3]. Thanks to its highly flexible structure, and the presence of several binding sites that are able to accommodate a variety of small molecules, SA is also the major facilitator of vascular drug transport. Up to now, ten binding sites within albumin have been characterized as drug sites, and nine of these have been demonstrated to bind at least three FDA-approved drugs[4]. Due to the high degree of structural conservation between mammalian albumins, non-human albumins, such as bovine serum albumin, or animal models, are often used to understand human albumin-drug interactions.
. Remember to drag the structures with the mouse to rotate them. Albumin subdomains are each shown in a different color. Roman numerals (I, II, III) are associated with domains and letters (e.g., IB) with subdomains. Ketoprofen molecules are shown with atoms in white spheres.
Ketoprofen binding sites in HSA (PDB ID: 7jwn):
in HSA (PDB ID: 7jwn) and LSA (PDB ID: 6ock). (S)-Ketoprofen molecule and molecule of a fatty acid bound to HSA are shown in stick representation with oxygen
atoms in red and carbon atoms in yellow, while a molecule of (S)-ketoprofen bound to LSA is shown in stick representation with oxygen atoms in red and carbon atoms in gray.
Superposition of structure of the HSA-ketoprofen complex (cartoon shown in gray) with the following complexes:
The results reported herein provide insight into the circulatory transport of ketoprofen, a popular nonsteroidal anti-inflammatory drug (NSAID), across species. The structure of the ketoprofen complex with human SA revealed that four ketoprofen molecules bind to three distinct sites within SA, which only partially overlap with sites previously reported to bind ketoprofen in SAs from other species. We explored the reasons for the observed differences, including identifying residues and interactions required for ketoprofen binding at specific sites and the influence of metabolites and components of crystallization solution on drug binding. The presented results reveal that the drug-binding properties of albumins cannot be easily predicted based only on a complex of albumin from another organism and the conservation of drug sites between species. This work shows that understanding organism-dependent differences is essential for assessing the suitability of particular albumins for structural or biochemical studies.
References
- ↑ Czub MP, Stewart AJ, Shabalin IG, Minor W. Organism-specific differences in the binding of ketoprofen to serum albumin. IUCrJ. 2022 Jul 16;9(Pt 5):551-561. doi: 10.1107/S2052252522006820. eCollection , 2022 Sep 1. PMID:36071810 doi:http://dx.doi.org/10.1107/S2052252522006820
- ↑ Doweiko JP, Nompleggi DJ. Role of albumin in human physiology and pathophysiology. JPEN J Parenter Enteral Nutr. 1991 Mar-Apr;15(2):207-11. doi: , 10.1177/0148607191015002207. PMID:2051560 doi:http://dx.doi.org/10.1177/0148607191015002207
- ↑ Peters TJT. All About Albumin: Biochemistry, Genetics, and Medical Applications. 1st ed. Academic Press; 1995 http://linkinghub.elsevier.com/retrieve/pii/B9780125521109X50004
- ↑ Czub MP, Handing KB, Venkataramany BS, Cooper DR, Shabalin IG, Minor W. Albumin-Based Transport of Nonsteroidal Anti-Inflammatory Drugs in Mammalian Blood Plasma. J Med Chem. 2020 Jul 9;63(13):6847-6862. doi: 10.1021/acs.jmedchem.0c00225. Epub , 2020 Jun 17. PMID:32469516 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c00225
