Abstract

Human serum albumin (HSA) is a monomeric, globular, multi-carrier and the most abundant protein in the blood. HSA displays multiple ligand binding sites with extraordinary binding capacity for a wide range of ions and molecules. For decades, HSA's ability to bind to various ligands has led many scientists to study its physiological properties and protein structure; indeed, a better understanding of HSA-ligand interactions in human blood, at the atomic level, will likely foster the development of more potent, and overall more performant, diagnostic and therapeutic tools against serious human disorders such as diabetes, cardiovascular disorders, and cancer. Here, we present a concise overview of the current knowledge of HSA's structural characteristics, and its coordination chemistry with transition metal ions, within the scope and limitations of current techniques and biophysical methods to reach atomic resolution in solution and in blood serum. We also highlight the overwhelming need of a detailed atomistic understanding of HSA dynamic structures and interactions that are transient, weak, multi-site and multi-step, and allosterically affected by each other. Considering the fact that HSA is a current clinical tool for drug delivery systems and a potential contender as molecular cargo and nano-vehicle used in biophysical, clinical and industrial fields, we underline the emerging need for novel approaches to target the dynamic functional coordination chemistry of the human blood serum albumin in solution, at the atomic level.

Highlights

  • Human serum albumin (HSA) is a monomeric, globular, multi-carrier and the most abundant protein in the blood

  • We summarize the current knowledge in high-resolution HSA coordination chemistry; we emphasize the overwhelming need for a detailed atomistic understanding of HSA dynamic structures and interactions, and the impact of the various endogenous and exogenous ligands and transition metal ions on the human serum albumin structure and dynamics, under conditions as close as possible to physiological conditions

  • In 2016, the combination of the above techniques delivered first long-awaited structural details on the primary Zn(II) ion binding site in HSA. This constituted a substantial achievement, one needs take into account that the HSA:Zn(II) complex was crystallized under non-physiological conditions, at pH 9

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Summary

Introduction – HSA the multitudinous protein “sponge”

Human serum albumin (HSA) accounts for over 60% (by mass) of human blood plasma proteins. By integrating our knowledge of contemporary molecular biophysics with that acquired in the medical field, we will likely be able, in the future, to directly monitor the atomistic details of HSA in human blood serum and correlate them with various states of health and disease. In many ways, such a dynamic functional high-resolution coordination chemistry of blood plasma HSA would be the realization of “the American dream of contemporary bioinorganic coordination chemistry”, providing us with an unparalleled understanding of molecular mechanisms, and, as a long-term goal, much more efficient approaches to therapeutic and diagnostic applications

Dynamic structures of heart-shaped human serum albumin
C B-factor
HSA interactome - from biophysics to medical diagnostics
Endogenous ligands
Essential metal ions
Bilirubin binding site
Exogenous ligands
3.11. Metallodrugs
3.12. Toxic metal ions
Findings
Summary
Full Text
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