5ID7

Crystal structure of human serum albumin in complex with phosphorodithioate derivative of myristoyl cyclic phosphatidic acid (cPA)

Summary for 5ID7

• Entry DOI: 10.2210/pdb5id7/pdb
• Descriptor: Serum albumin, (4S)-2-sulfanylidene-4-[(tetradecanoyloxy)methyl]-1,3,2lambda~5~-dioxaphospholane-2-thiolate, TRIETHYLENE GLYCOL, ... (5 entities in total)
• Functional Keywords: helical, three-domain protein, serum albumin, transport protein, drugs delivery, cyclic phosphatidic acid, lysophospholipid
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted: P02768
• Total number of polymer chains: 2
• Total formula weight: 136284.54

Authors

Sekula, B.,Bujacz, A.,Rytczak, P.,Bujacz, G. (deposition date: 2016-02-24, release date: 2016-05-11, Last modification date: 2024-11-13)

Primary citation

Sekula, B.,Ciesielska, A.,Rytczak, P.,Koziokiewicz, M.,Bujacz, A.
Structural evidence of the species-dependent albumin binding of the modified cyclic phosphatidic acid with cytotoxic properties.
Biosci.Rep., 36:-, 2016

PubMed Abstract: Cyclic phosphatidic acids (cPAs) are naturally occurring, very active signalling 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. 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 (LPLs). 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 (PC) cells. Myr-2S-cPA reduces cancer cell viability in a dose-dependent manner, with IC50 value of 29.0 μM after 24 h incubation, which is almost 30% lower than IC50 of single substituted phosphorothioate cPA. 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 LPL analogue. HSA binds three molecules of Myr-2S-cPA, whereas ESA only one. Moreover, none of the identified Myr-2S-cPA binding sites overlap in both albumins.

PubMed: 27129297
DOI: 10.1042/BSR20160089

Experimental method

X-RAY DIFFRACTION (2.26 Å)