title: Dual binding of an antibody and a small molecule increases the stability of TERRA G-quadruplex.
abstract: In investigating the binding interactions between the human telomeric RNA (TERRA) G-quadruplex (GQ) and its ligands, it was found that the small molecule carboxypyridostatin (cPDS) and the GQ-selective antibody BG4 simultaneously bind the TERRA GQ. We previously showed that the overall binding affinity of BG4 for RNA GQs is not significantly affected in the presence of cPDS. However, single-molecule mechanical unfolding experiments revealed a population (48%) with substantially increased mechanical and thermodynamic stability. Force-jump kinetic investigations suggested competitive binding of cPDS and BG4 to the TERRA GQ. Following this, the two bound ligands slowly rearrange, thereby leading to the minor population with increased stability. Given the relevance of G-quadruplexes in the regulation of biological processes, we anticipate that the unprecedented conformational rearrangement observed in the TERRA-GQ-ligand complex may inspire new strategies for the selective stabilization of G-quadruplexes in cells.
authors.affiliation: Department of Chemistry and Biochemistry, Kent State University, Kent, OH 44242 (USA).
authors.forename: Philip M
authors.initials: PM
authors.lastname: Yangyuoru
authors.forename: Marco
authors.initials: M
authors.lastname: Di Antonio
authors.forename: Chiran
authors.initials: C
authors.lastname: Ghimire
authors.forename: Giulia
authors.initials: G
authors.lastname: Biffi
authors.forename: Shankar
authors.initials: S
authors.lastname: Balasubramanian
authors.forename: Hanbin
authors.initials: H
authors.lastname: Mao
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry / Q000378:metabolism*; D000906:Antibodies / Q000276:immunology*; D054856:G-Quadruplexes; D006801:Humans; D008024:Ligands; D009690:Nucleic Acid Conformation; D052898:Optical Tweezers; D010848:Picolinic Acids / Q000737:chemistry / Q000378:metabolism*; D012313:RNA / Q000737:chemistry; D016615:Telomere / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D000634:Aminoquinolines; D000906:Antibodies; D008024:Ligands; D010848:Picolinic Acids; C567962:pyridostatin; D012313:RNA
keywords: G-quadruplexes; RNA structures; ligand effects; optical traps; single-molecule studies