Dataset Information

Structural and thermodynamic consequences of the replacement of zinc with environmental metals on estrogen receptor ?-DNA interactions.

ABSTRACT: Estrogen receptor ? (ER?) acts as a transcription factor by virtue of the ability of its DNA-binding (DB) domain, comprised of a tandem pair of zinc fingers, to recognize the estrogen response element within the promoters of target genes. Herein, using an array of biophysical methods, we probe the structural consequences of the replacement of zinc within the DB domain of ER? with various environmental metals and their effects on the thermodynamics of binding to DNA. Our data reveal that whereas the DB domain reconstituted with divalent ions of zinc, cadmium, mercury, and cobalt binds to DNA with affinities in the nanomolar range, divalent ions of barium, copper, iron, lead, manganese, nickel, and tin are unable to regenerate DB domain with DNA-binding potential, although they can compete with zinc for coordinating the cysteine ligands within the zinc fingers. We also show that the metal-free DB domain is a homodimer in solution and that the binding of various metals only results in subtle secondary and tertiary structural changes, implying that metal coordination may only be essential for binding to DNA. Collectively, our findings provide mechanistic insights into how environmental metals may modulate the physiological function of a key nuclear receptor involved in mediating a plethora of cellular functions central to human health and disease.

SUBMITTER: Deegan BJ

PROVIDER: S-EPMC3205435 | biostudies-literature | 2011 Nov-Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Structural and thermodynamic consequences of the replacement of zinc with environmental metals on estrogen receptor α-DNA interactions.

Deegan Brian J BJ Bona Anna M AM Bhat Vikas V Mikles David C DC McDonald Caleb B CB Seldeen Kenneth L KL Farooq Amjad A

Journal of molecular recognition : JMR 20111101 6

Estrogen receptor α (ERα) acts as a transcription factor by virtue of the ability of its DNA-binding (DB) domain, comprised of a tandem pair of zinc fingers, to recognize the estrogen response element within the promoters of target genes. Herein, using an array of biophysical methods, we probe the structural consequences of the replacement of zinc within the DB domain of ERα with various environmental metals and their effects on the thermodynamics of binding to DNA. Our data reveal that whereas ...[more]

PMID: 22038807

Similar Datasets

Project description:The most frequently diagnosed cancers in women are the estrogen receptor (ER)-positive breast cancer subtypes, which are characterized by estrogen dependency for their growth. The mainstay of clinical treatment for this tumor relies on the modulation of ERα action or on the suppression of estrogen biosynthesis via the administration of Selective ERα Modulators/Down-regulators (SERMs/SERDs) or aromatase inhibitors, respectively. Nevertheless, de novo and acquired resistance to these therapies frequently occurs and represents a major clinical concern for patient survival. Recently, somatic mutations affecting the hormone-binding domain of ERα (i.e., Y537S, Y537N, D538G) have been associated with endocrine resistance, disease relapse and increased mortality rates. Hence, devising novel therapies against these ERα isoforms represents a daunting challenge. Here, we identified five molecules active on recurrent Y537S ERα polymorphism by employing in silico virtual screening on commercial databases of molecules, complemented by ER-transactivation and MTT assays in MCF7 and MDA-MB-231 breast cancer cells expressing wild type or mutated ERα. Among them, one molecule selectively targets Y537S ERα without inducing any cytotoxicity in breast cell lines. Multi-microseconds (4.5 μs) of biased and unbiased molecular dynamics provided an atomic-level picture of the structural, thermodynamics (i.e., binding free energies) and the kinetic (i.e., dissociation free energy barriers) of these active ligands as compared to clinically used SERM/SERDs upon binding to wild type and distinct ERα variants (Y537S, Y537N, D538G). This study contributes to a dissection of the key molecular traits needed by drug-candidates to hamper the agonist (active)-like conformation of ERα, normally selected by those polymorphic variants. This information can be useful to discover mutant specific drug-candidates, enabling to move a step forward toward tailored approaches for breast cancer treatment.

Dataset Information

Structural and thermodynamic consequences of the replacement of zinc with environmental metals on estrogen receptor ?-DNA interactions.

Publications

Structural and thermodynamic consequences of the replacement of zinc with environmental metals on estrogen receptor α-DNA interactions.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets