title: Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain.
abstract: Overproduction of immunoglobulin light chains leads to systemic amyloidosis, a lethal disease characterized by the formation of amyloid fibrils in patients' tissues. Excess light chains are in equilibrium between dimers and less stable monomers which can undergo irreversible aggregation to the amyloid state. The dimers therefore must disassociate into monomers prior to forming amyloid fibrils. Here we identify ligands that inhibit amyloid formation by stabilizing the Mcg light chain variable domain dimer and shifting the equilibrium away from the amyloid-prone monomer.
authors.affiliation: Department of Biological Chemistry, Howard Hughes Medical Institute, UCLA, Los Angeles, United States.|UCLA-DOE Institute for Genomics and Proteomics, Los Angeles, United States.|Department of Chemistry and Biochemistry, UCLA, Los Angeles, United States.
authors.forename: Boris
authors.initials: B
authors.lastname: Brumshtein
authors.affiliation: Department of Biological Chemistry, Howard Hughes Medical Institute, UCLA, Los Angeles, United States.|UCLA-DOE Institute for Genomics and Proteomics, Los Angeles, United States.|Department of Chemistry and Biochemistry, UCLA, Los Angeles, United States.
authors.forename: Shannon R
authors.identifier: http://orcid.org/0000-0002-5142-0190
authors.initials: SR
authors.lastname: Esswein
authors.affiliation: Department of Biological Chemistry, Howard Hughes Medical Institute, UCLA, Los Angeles, United States.|UCLA-DOE Institute for Genomics and Proteomics, Los Angeles, United States.|Department of Chemistry and Biochemistry, UCLA, Los Angeles, United States.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Salwinski
authors.affiliation: UCLA-DOE Institute for Genomics and Proteomics, Los Angeles, United States.|Department of Chemistry and Biochemistry, UCLA, Los Angeles, United States.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Phillips
authors.affiliation: Department of Biological Chemistry, Howard Hughes Medical Institute, UCLA, Los Angeles, United States.|UCLA-DOE Institute for Genomics and Proteomics, Los Angeles, United States.|Department of Chemistry and Biochemistry, UCLA, Los Angeles, United States.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Ly
authors.affiliation: Department of Biological Chemistry, Howard Hughes Medical Institute, UCLA, Los Angeles, United States.|UCLA-DOE Institute for Genomics and Proteomics, Los Angeles, United States.|Department of Chemistry and Biochemistry, UCLA, Los Angeles, United States.
authors.forename: Duilio
authors.initials: D
authors.lastname: Cascio
authors.affiliation: Department of Biological Chemistry, Howard Hughes Medical Institute, UCLA, Los Angeles, United States.|UCLA-DOE Institute for Genomics and Proteomics, Los Angeles, United States.|Department of Chemistry and Biochemistry, UCLA, Los Angeles, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Sawaya
authors.affiliation: Department of Biological Chemistry, Howard Hughes Medical Institute, UCLA, Los Angeles, United States.|UCLA-DOE Institute for Genomics and Proteomics, Los Angeles, United States.|Department of Chemistry and Biochemistry, UCLA, Los Angeles, United States.
authors.forename: David S
authors.initials: DS
authors.lastname: Eisenberg
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors*; D007147:Immunoglobulin Light Chains / Q000378:metabolism*; D008024:Ligands
chemical_list: D000682:Amyloid; D007147:Immunoglobulin Light Chains; D008024:Ligands
keywords: Bnece-Jones proteins; E. coli; amyloid; biochemistry; biophysics; light-chain variable domains; multiple myeloma; protein aggregation; structural biology