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Crystal structure of human serum albumin in complex with phosphorodithioate derivative of myristoyl cyclic phosphatidic acid (cPA)Crystal structure of human serum albumin in complex with phosphorodithioate derivative of myristoyl cyclic phosphatidic acid (cPA)
Structural highlights
DiseaseALBU_HUMAN Defects in ALB are a cause of familial dysalbuminemic hyperthyroxinemia (FDH) [MIM:103600. FDH is a form of euthyroid hyperthyroxinemia that is due to increased affinity of ALB for T(4). It is the most common cause of inherited euthyroid hyperthyroxinemia in Caucasian population.[1] [2] [3] [4] FunctionALBU_HUMAN Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc.[5] Publication Abstract from PubMedCyclic phosphatidic acids (cPAs) are naturally occurring, very active signaling molecules, which are involved in several pathological states, such as cancer, diabetes, or obesity. As molecules of highly lipidic character found in the circulatory system, cPAs are bound and transported by the main extracellular lipid binding protein - serum albumin.<br />Here, we present the detailed interactions between human serum albumin (HSA) and equine serum albumin (ESA) with a derivative of cPA, 1-O-myristoyl-sn-glycerol-2,3-cyclic phosphorodithioate (Myr-2S-cPA). Initial selection of the ligand used for the structural study was made by the analysis of the therapeutically promising properties of the sulfur containing analogues of cPA in respect to the unmodified lysophospholipids. Substitution of one or two non-bridging oxygen atoms in the phosphate group with one or two sulfur atoms increases the cytotoxic effect of cPAs up to 60% on the human prostate cancer cells. Myr-2S-cPA reduces cancer cell viability in a dose-dependent manner, with IC50 value of 29.0 muM after 24h incubation, which is almost 30% lower than IC50 of single substituted phosphorothioate cPA.<br />Although, the structural homology between HSA and ESA is big, their crystal complexes with Myr-2S-cPA demonstrate significantly different mode of binding of this lysophospholipid analogue. HSA binds three molecules of Myr-2S-cPA, while ESA only one. Moreover, none of the identified Myr-2S-cPA binding sites overlap in both albumins. Structural evidence of the species-dependent albumin binding of the modified cyclic phosphatidic acid with cytotoxic properties.,Sekula B, Ciesielska A, Rytczak P, Koziolkiewicz M, Bujacz A Biosci Rep. 2016 Apr 15. pii: BSR20160089. PMID:27129297[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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