Human serum albumin (HSA) is an abundant plasma protein that is responsible for the transport of a range of insoluble endogenous compounds including fatty acids, hormones and toxic metabolites such as bilirubin.Albumin also binds an impressive array of drugs in two primary sites (I and II) and much of the clinical and pharmaceutical interest in the protein derives from its effect on drug pharmacokinetics.HSA is a monomer that contains three homologous helical domains (I-III) each divided into two subdomains (A and B).Previously we determined the first high-resolution structures of HSA complexed with fatty acids and revealed the molecular interactions between HSA and its primary ligand.Here we present a crystallographic study of site I drugs and drug-analogues complexed with HSA-myristate.The structures confirm that phenylbutazone, oxyphenbutazone, azapropazone, iodipamide, dansyl-L-arginine, indomethacin, warfarin, triiodobenzoic acid and di-iodosalicyclic acid all bind at site I (subdomain IIA) in the presence of fatty acids.Our studies have also revealed the presence of additional drug sites for some of these compounds in subdomains IB and IIIB.The crystal structures throw new light on the molecular details of HSA-drug interaction and provide a new understanding of the structural basis of the very broad drug-binding specificity of the protein.By using a range of site I drugs we have been able to probe both common and distinct modes of interaction at site I; it is apparent that side-chain flexibility is important for accommodation of a range of different compounds in this binding site.
Antimicrobial resistance (particularly through extended-spectrum β-lactamase and aminoglycoside-modifying enzyme production) in neonatal sepsis is a global problem, particularly in low- and middle-income countries, with significant mortality rates. High rates of resistance are reported for the current WHO-recommended first-line antibiotic regimen for neonatal sepsis, i.e., ampicillin and gentamicin.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
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