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Dual binding of an antibody and a small molecule increases the stability of TERRA G-quadruplex.


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Authors

Yangyuoru, Philip M 
Ghimire, Chiran 
Balasubramanian, Shankar  ORCID logo  https://orcid.org/0000-0002-0281-5815

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.

Description

Keywords

G-quadruplexes, RNA structures, ligand effects, optical traps, single-molecule studies, Aminoquinolines, Antibodies, G-Quadruplexes, Humans, Ligands, Nucleic Acid Conformation, Optical Tweezers, Picolinic Acids, RNA, Telomere, Thermodynamics

Journal Title

Angew Chem Int Ed Engl

Conference Name

Journal ISSN

1433-7851
1521-3773

Volume Title

54

Publisher

Wiley
Sponsorship
H.M. acknowledges support from NSF CHE-1026532. The Balasubramanian lab is supported by programme funding from Cancer Research UK.