Abstract
Gemfibrozil (GEM) is an orally administered lipid-regulating fibrate derivative drug sold under the brand name Lopid®, among others. Since its approval in the early 80s, GEM has been largely applied to treat hypertriglyceridemia and other disorders of lipid metabolism. Though generally well tolerated, GEM can alter the distribution and the free, active concentration of some co-administered drugs, leading to adverse effects. Most of them appear to be related to the ability of GEM to bind with high affinity human serum albumin (HSA), the major drug-carrier protein in blood plasma. Here, we report the crystal structure of HSA in complex with GEM. Two binding sites have been identified, namely Sudlow’s binding sites I (FA7) and II (FA3–FA4). A comparison of the crystal structure of HSA in complex with GEM with those of other previously described HSA–drug complexes enabled us to appreciate the analogies and differences in their respective binding modes. The elucidation of the molecular interaction between GEM and HSA might offer the basis for the development of novel GEM derivatives that can be safely and synergistically co-administered with other drugs, enabling augmented therapeutic efficacies.
Highlights
Overview of the Crystal Structure of human serum albumin (HSA) in Complex with GEM LigandsTo unveil the binding mode of HSA to GEM, we applied X-ray crystallography and determined the structure of the complex (Figure 1a,b)
Present address: The Armenise-Harvard Laboratory of Structural Biology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy
This process results in decreased levels of both serum triglycerides and serum low-density lipoproteins (LDL) as well as an increase in high-density lipoproteins (HDL) [5,6]
Summary
To unveil the binding mode of HSA to GEM, we applied X-ray crystallography and determined the structure of the complex (Figure 1a,b). Two binding sites are occupied by GEM and are located at the Sudlow’s sites I (FA7, subdomain IIA) and II (FA3-FA4, subdomain IIIA; Figure 1). Electron density maps and refined occupancies of the two sites revealed full saturation (100%) for FA4, while those for FA7 revealed slightly less occupation (74%). The remaining four HSA-binding sites (FA1, FA2, FA5, and FA6) are occupied by myristic acid (Myr) and/or other precipitating molecules used in crystallisation trials. Structure of HSA Figure in complex with GEM. GEM1 ligand contoured at 2.5σ and(b) shown crystal structure of the HSA-GEM complex (white) shown in two orientations In two orientations (90 rotation); (b) crystal structure of the HSA-GEM complex (white) shown in.
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