title: Evidence that Chemical Chaperone 4-Phenylbutyric Acid Binds to Human Serum Albumin at Fatty Acid Binding Sites.
abstract: Endoplasmic reticulum stress elicits unfolded protein response to counteract the accumulating unfolded protein load inside a cell. The chemical chaperone, 4-Phenylbutyric acid (4-PBA) is a FDA approved drug that alleviates endoplasmic reticulum stress by assisting protein folding. It is found efficacious to augment pathological conditions like type 2 diabetes, obesity and neurodegeneration. This study explores the binding nature of 4-PBA with human serum albumin (HSA) through spectroscopic and molecular dynamics approaches, and the results show that 4-PBA has high binding specificity to Sudlow Site II (Fatty acid binding site 3, subdomain IIIA). Ligand displacement studies, RMSD stabilization profiles and MM-PBSA binding free energy calculation confirm the same. The binding constant as calculated from fluorescence spectroscopic studies was found to be k(PBA) = 2.69 x 10(5) M(-1). Like long chain fatty acids, 4-PBA induces conformational changes on HSA as shown by circular dichroism, and it elicits stable binding at Sudlow Site II (fatty acid binding site 3) by forming strong hydrogen bonding and a salt bridge between domain II and III of HSA. This minimizes the fluctuation of HSA backbone as shown by limited conformational space occupancy in the principal component analysis. The overall hydrophobicity of W214 pocket (located at subdomain IIA), increases upon occupancy of 4-PBA at any FA site. Descriptors of this pocket formed by residues from other subdomains largely play a role in compensating the dynamic movement of W214.
authors.affiliation: 206, Structural Biology Lab, Center for Biomedical Research, Division of Biomedical Sciences, School of Bio Sciences and Technology, VIT University, Vellore-632014, Tamil Nadu, India.
authors.forename: Debasish
authors.initials: D
authors.lastname: Roy
authors.affiliation: 206, Structural Biology Lab, Center for Biomedical Research, Division of Biomedical Sciences, School of Bio Sciences and Technology, VIT University, Vellore-632014, Tamil Nadu, India.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: 206, Structural Biology Lab, Center for Biomedical Research, Division of Biomedical Sciences, School of Bio Sciences and Technology, VIT University, Vellore-632014, Tamil Nadu, India.
authors.forename: Joel
authors.initials: J
authors.lastname: James
authors.affiliation: 206, Structural Biology Lab, Center for Biomedical Research, Division of Biomedical Sciences, School of Bio Sciences and Technology, VIT University, Vellore-632014, Tamil Nadu, India.
authors.forename: Mohamed Sham
authors.initials: MS
authors.lastname: Shihabudeen
authors.affiliation: 206, Structural Biology Lab, Center for Biomedical Research, Division of Biomedical Sciences, School of Bio Sciences and Technology, VIT University, Vellore-632014, Tamil Nadu, India.
authors.forename: Shweta
authors.initials: S
authors.lastname: Kulshrestha
authors.affiliation: 206, Structural Biology Lab, Center for Biomedical Research, Division of Biomedical Sciences, School of Bio Sciences and Technology, VIT University, Vellore-632014, Tamil Nadu, India.
authors.forename: Varun
authors.initials: V
authors.lastname: Goel
authors.affiliation: 206, Structural Biology Lab, Center for Biomedical Research, Division of Biomedical Sciences, School of Bio Sciences and Technology, VIT University, Vellore-632014, Tamil Nadu, India.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Thirumurugan
mesh_terms: D001665:Binding Sites; D005227:Fatty Acids / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008024:Ligands; D056004:Molecular Dynamics Simulation; D018696:Neuroprotective Agents / Q000737:chemistry*; D010654:Phenylbutyrates / Q000737:chemistry*; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012709:Serum Albumin / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D005227:Fatty Acids; D008024:Ligands; D018696:Neuroprotective Agents; D010654:Phenylbutyrates; D012709:Serum Albumin; C075773:4-phenylbutyric acid