title: Subdomain IB is the third major drug binding region of human serum albumin: toward the three-sites model.
abstract: According to the conventional view, noncovalent association of small molecules with human serum albumin (HSA) occurs principally at the so-called Sudlow's sites located in subdomain IIA and IIIA. By employing a circular dichroism (CD) spectroscopic approach, it is shown that biliverdin is the specific CD label of an additional drug binding area in subdomain IB. CD competition experiments disclosed the entrapment of a diverse assortment of acidic, neutral, and basic molecules within subdomain IB including anticancer agents (camptothecin, doxorubicin, daunorubicin, teniposide, suramin, tyrosine kinase inhibitors), anticoagulants (dicoumarol), various steroids (bile acids, carbenoxolone), nonsteroidal antiinflammatory drugs, natural substances (aristolochic acid, glycyrrhetinic acid), and synthetic dyes (methyl orange, azocarmine B). These finding imply that subdomain IB can be considered as the third major drug binding region of HSA featured with promiscuous ligand recognition ability. Additionally, subdomain IB is allosterically coupled with the Sudlow's sites, the ligand binding of which is shown to alter the HSA binding mode and affinity of biliverdin and hemin. Brief case studies are presented to illustrate how the evaluation of spectral changes of tetrapyrrole CD probes gains new insight into the HSA binding properties of endogenous as well as pharmaceutical compounds.
authors.affiliation: Laboratory of Chemical Pharmacology, Institute of Molecular Pharmacology, Research Centre for Natural Sciences, H-1025 Budapest, Pusztaszeri út 59-67, Hungary. zsila.ferenc@ttk.mta.hu
authors.forename: Ferenc
authors.initials: F
authors.lastname: Zsila
mesh_terms: D000495:Allosteric Site; D001664:Biliverdine / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D002942:Circular Dichroism; D005227:Fatty Acids / Q000378:metabolism; D006427:Hemin / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism*; D013053:Spectrophotometry
chemical_list: D005227:Fatty Acids; D008024:Ligands; D004364:Pharmaceutical Preparations; D012709:Serum Albumin; D006427:Hemin; D001664:Biliverdine