Structural Basis of the Drug-Binding Specificity of Human Serum Albumin.

Human serum albumin: from bench to bedside.

Human serum albumin (HSA), the most prominent protein in plasma, binds different classes of ligands at multiple sites HSA provides a depot for many compounds, affects pharmacokinetics of many drugs, holds some ligands in a strained orientation providing their metabolic modification, renders potential toxins harmless transporting them to disposal sites, accounts for most of the antioxidant capacity of human serum, and acts as a NO-carrier The globular domain structural organization of monomeric HSA is at the root of its allosteric properties which are reminiscent of those of multimeric proteins Here, structural, functional, biotechnological, and biomedical aspects of ligand binding to HSA are summarized

https://iubmb.onlinelibrary.wiley.com/doi/epdf/10.1080/15216540500404093

The extraordinary ligand binding properties of human serum albumin

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.20720

Albumin: biochemical properties and therapeutic potential.

Serum albumin first appeared in early vertebrates and is present in the plasma of all mammals. Its canonical structure supported by a conserved set of disulfide bridges is maintained in all mammalian serum albumins and any changes in sequence are highly correlated with evolution of the species. Previous structural investigations of mammalian serum albumins have only concentrated on human serum albumin (HSA), most likely as a consequence of crystallization and diffraction difficulties. Here, the crystal structures of serum albumins isolated from bovine, equine and leporine blood plasma are reported. The structure of bovine serum albumin (BSA) was determined at 2.47 A resolution, two crystal structures of equine serum albumin (ESA) were determined at resolutions of 2.32 and 2.04 A, and that of leporine serum albumin (LSA) was determined at 2.27 A resolution. These structures were compared in detail with the structure of HSA. The ligand-binding pockets in BSA, ESA and LSA revealed different amino-acid compositions and conformations in comparison to HSA in some cases; however, much more significant differences were observed on the surface of the molecules. BSA, which is one of the most extensively utilized proteins in laboratory practice and is used as an HSA substitute in many experiments, exhibits only 75.8% identity compared with HSA. The higher resolution crystal structure of ESA highlights the binding properties of this protein because it includes several bound compounds from the crystallization solution that provide additional structural information about potential ligand-binding pockets.

Structures of bovine, equine and leporine serum albumin.

The atomic structure of human methemalbumin at 1.9 A.

Structural studies of several clinically important oncology drugs in complex with human serum albumin.

Ferritin is the major iron-storage protein present in all cells. It generally contains 24 subunits, with different ratios of heavy chain (H) to light chain (L), in the shape of a hollow sphere hosting up to 4500 ferric Fe atoms inside. H-rich ferritins catalyse the oxidation of iron(II), while L-rich ferritins promote the nucleation and storage of iron(III). Several X-­ray structures have been determined, including those of L-­chain ferritins from horse spleen (HoSF), recombinant L-­chain ferritins from horse (HoLF), mouse (MoLF) and bullfrog (BfLF) as well as recombinant human H-chain ferritin (HuHF). Here, structures have been determined of two crystal forms of recombinant human L-chain ferritin (HuLF) obtained from native and perdeuterated proteins. The structures show a cluster of acidic residues at the ferrihydrite nucleation site and at the iron channel along the threefold axis. An ordered Cd2+ structure is observed within the iron channel, offering further insight into the route and mechanism of iron transport into the capsid. The loop between helices D and E, which is disordered in many other L-­chain structures, is clearly visible in these two structures. The crystals generated from perdeuterated HuLF will be used for neutron diffraction studies.

Structure of human ferritin L chain.

A Chalaropsis lysozyme (Lysozyme Ch) is provided which has a corrected amino acid sequence and which can be utilized to prepare recombinant proteins having higher activity than those proteins prepared using the incorrect sequence. Methods are also provided to reduce immunogenicity or increase half-life of the lysozyme. The lysozyme Ch of the present invention will be extremely useful in killing bacteria, particularly resistance strains such as MRSA and VISA, and the enzyme can be utilized in a variety of settings wherein bacterial infection has been a particular problem such as the hospital setting or in veterinary applications, and can also be used as an effective means of combating bioterror agents.

Chalaropsis lysozyme protein and its method of use in anti-bacterial applications

A method is provided for evaluating drug compounds based on their binding properties to human serum albumin wherein structural information at particular albumin binding regions is entered into a computer database and assessed with regard to particular contacting binding residues located in accordance with the invention. The information obtained through the computer database is thus useful in assessing and predicting drug interactions at albumin binding sites. Further, protein fragments including one or more albumin binding sites are provided which can be used in methods of assessing and designing drugs.

Zhongmin Wang

Papers

The atomic structure of human methemalbumin at 1.9 A.

Structural studies of several clinically important oncology drugs in complex with human serum albumin.

Structure of human ferritin L chain.

Chalaropsis lysozyme protein and its method of use in anti-bacterial applications

Atomic coordinates of albumin drug complexes and method of use of pharmaceutical development