Allosteric Modulation of Drug Binding to Human Serum Albumin

Abstract

Human serum albumin (HSA), the most prominent protein in plasma, is best known for its extraordinary ligand binding capacity. The three homologous domains of HSA (labeled I, II, and III), each in turn composed of two subdomains (named A and B), give rise to the three-dimensional structure of HSA. This flexible structural organization allows the protein structure to adapt to a variety of ligands. As conformational adaptability of HSA extends well beyond the immediate vicinity of the binding site(s), cooperativity and allosteric modulation arise among binding sites; this makes HSA similar to a multimeric protein. Although kinetic and thermodynamic parameters for ligand binding to HSA calculated by quantitative structure-activity relationship models are in excellent agreement with those obtained in vitro, cooperative and allosteric equilibria between different binding sites and competition between drugs or between drugs and endogenous ligands make difficult the interpretation of HSA binding properties in vivo. Binding of exogenous and endogenous ligands to HSA appears to be relevant in drug therapy and management. Here, the allosteric modulation of drug binding to HSA is briefly reviewed.

Evidence for pH-dependent multiple conformers in iron(II) heme–human serum albumin: spectroscopic and kinetic investigation of carbon monoxide binding

“…In addition, the growing importance of the diatomic ligand CO as a gas transducer involved in the signaling related to reactive oxygen species [60] renders these kinetic investigations of physiopathological relevance. Thus, the role played by heme-HSA in the detoxification process is significantly enhanced by the fact that the amount of heme-HSA increases significantly under pathological conditions [9,10,61,62] owing to the function of HSA as a heme scavenger from HDL and LDL, impairing their oxidation [8,48,49].…”

“…Among others, HSA appears (1) to be an important determinant of the pharmacokinetic behavior of many drugs, (2) to account for most of the antioxidant capacity of human serum, and (3) to display enzymatic properties [1][2][3][4][5][6][7][8][9][10][11].…”

“…Terminal regions of sequential domains contribute to the formation of interdomain h10-h1 helices linking subdomain IB to subdomain IIA and subdomain IIB to subdomain IIIA, respectively ( Fig. 1) [2,3,[10][11][12][13][14][15][16][17].…”

Reversible two-step unfolding of heme–human serum albumin: a 1H-NMR relaxometric and circular dichroism study

“…Each domain is formed by two separate subdomains (named A and B), connected by a random coil (Fig. 1) [1][2][3][4][5].…”

Effect of tanshinone IIA on the noncovalent interaction between warfarin and human serum albumin studied by electrospray ionization mass spectrometry

“…It also binds a wide variation of drugs and xenobiotics to facilitate their transport throughout the circulatory system [12][13][14][15][16][17][18]. WAR, a highly protein-bound drug, binds to the protein through site 1, which is a preformed binding pocket within the core of subdomain IIA of human serum albumin (HSA) [19,20]. Danshen is also strongly proteinbound and albumin is the major serum protein that binds to Danshen [21].…”