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X-ray study of human serum albumin complexed with camptothecinX-ray study of human serum albumin complexed with camptothecin
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 PubMedBACKGROUND: Serum albumin is a major pharmacokinetic effector of drugs. To gain further insight into albumin binding chemistry, the crystal structures of six oncology agents were determined in complex with human serum albumin at resolutions of 2.8 to 2.0A: camptothecin, 9-amino-camptothecin, etoposide, teniposide, bicalutamide and idarubicin. METHODS: Protein crystal growth and low temperature X-ray crystallography RESULTS: These large, complex drugs are all bound within the subdomain IB binding region which can be described as a hydrophobic groove formed by alpha-helices h7, h8 and h9 covered by the extended polypeptide L1. L1 creates a binding cavity with two access sites, one between loop L1 and alpha-helices h7 and h8 (distal site: IBd) and the other between L1 and alpha-helix h9 (proximal site: IBp). Camptothecin (2.4A) and 9 amino camptothecin (2.0A) are clearly bound as the open lactone form (IBp). Idarubicin (2.8A) binds in a DNA like dimer complex via an intermolecular pi stacking arrangement in IBd. Bicalutamide (2.4A) is bound in a folded intramolecular pi stacking arrangement between two aromatic rings in IBd similar to idarubicin. Teniposide (2.7A) and etoposide (2.7A), despite small chemical differences, are bound in two distinctly different sites at or near IB. Teniposide is internalized via primarily hydrophobic interactions and spans through both openings (IBp-d). Etoposide is bound between the exterior of IB and IIA and exhibits an extensive hydrogen bonding network. CONCLUSIONS: Subdomain IB is a major binding site for complex heterocyclic molecules. GENERAL SIGNIFICANCE: The structures have important implications for drug design and development. This article is part of a Special Issue entitled Serum Albumin. Structural studies of several clinically important oncology drugs in complex with human serum albumin.,Wang ZM, Ho JX, Ruble JR, Rose J, Ruker F, Ellenburg M, Murphy R, Click J, Soistman E, Wilkerson L, Carter DC Biochim Biophys Acta. 2013 Jul 6. pii: S0304-4165(13)00292-4. doi:, 10.1016/j.bbagen.2013.06.032. PMID:23838380[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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