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Understanding Ligand Binding Effects on the Conformation of Estrogen Receptor -DNA Complexes: A Combinational Quartz Crystal Microbalance with Dissipation and Surface Plasmon Resonance Study

Wendy Y. X. Peh ^*, Erik Reimhult , Huey Fang Teh ^*, Jane S. Thomsen  and Xiaodi Su ^*

^* Institute of Materials Research and Engineering, Singapore 117602; Swiss Federal Institute of Technology (ETHZ) Zurich, Laboratory for Surface Science and Technology, BioInterfaceGroup, CH-8093 Zurich, Switzerland; Genome Institute of Singapore, 60 Biopolis Street, Singapore 117528

Correspondence: Address reprint requests to Xiaodi Su, PhD, Tel.: 65-68748420; Fax: 65-68720785; E-mail: xd-su{at}imre.a-star.edu.sg.

Estrogen receptors are ligand-activated transcription factors that regulate gene expression by binding to specific DNA sequences. To date, the effect of ligands on the conformation of estrogen receptor (ER)-DNA complex remains a poorly understood issue. In our study, we are introducing the quartz crystal microbalance with dissipation monitoring (QCM-D) as a new alternative to study the conformational differences in protein-DNA complexes. Specifically, we have used QCM-D, in combination with surface plasmon resonance (SPR) spectroscopy, to monitor the binding of ER to a specific DNA (estrogen response element, ERE) and a nonspecific DNA in the presence of either the agonist ligand, 17b-estradiol, the partial antagonist ligand, 4-hydroxytamoxifen, or vehicle alone. Both with presence and absence of ligand, the specific ER-ERE complexes are observed to adopt a more compact conformation compared to nonspecific complexes. This observation is well correlated to the biophysical changes occurring during protein-DNA interaction shown by past structural and mechanism studies. Notably, pretreatment of ER with E2 and 4OHT affects not only the viscoelasticity and conformation of the protein-DNA complex but also ER binding capacity to immobilized ERE. These results affirm that ligands have remarkable effects on ER-DNA complexes. Understanding these effects will provide insight into how ligand binding promotes subsequent events required for gene transcription.

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