Human serum albumin (Sudlow I site) (HSA (Sudlow I))

Human serum albumin (HSA) is the most abundant protein in human blood plasma and serves as the primary carrier for a wide range of endogenous and exogenous compounds, including hormones, fatty acids, and pharmaceuticals [1, 1.4.2]. The Sudlow I site, also known as Drug Site 1 or the warfarin binding site, is a major binding pocket located within subdomain IIA of the HSA structure [1, 5]. This site is characterized by a large, flexible hydrophobic cavity that preferentially binds bulky heterocyclic anions and dicarboxylic acids [1.1.2, 2]. By sequestering these molecules, the Sudlow I site plays a pivotal role in modulating the pharmacokinetics and pharmacodynamics of many drugs, effectively controlling their free, active concentration in the circulation [3, 1.3.2]. Clinical conditions such as diabetes, renal failure, or liver disease can lead to post-translational modifications like glycation or changes in albumin levels, which alter the binding affinity of the Sudlow I site and can result in significant drug-drug interactions or therapeutic failure [4, 1.4.1].

Other names

Drug Site 1DS1Warfarin-azapropazone binding siteSubdomain IIA binding site

Drugs bind to the Sudlow I site through a combination of hydrophobic interactions and electrostatic forces, primarily involving residues such as Lys199 and Tyr150 [1, 2]. This binding sequesters the drugs within the plasma, thereby reducing their free, pharmacologically active concentration and extending their circulatory half-life [3, 5]. Additionally, the site can exhibit esterase-like catalytic activity and participate in allosteric regulation of other binding sites on the albumin molecule [2, 1.3.1].