Structure of the heterodimeric ecdysone receptor DNA-binding complex

Area of Science:

• Molecular Biology
• Structural Biology
• Endocrinology

Background:

• Ecdysteroids regulate insect development through the ecdysone receptor (EcR) and ultraspiracle (USP) heterodimer.
• This complex binds to specific DNA sequences known as IR-1 elements, which are characterized by inverted repeats.
• The heterodimeric DNA binding is a distinctive feature among nuclear receptors.

Purpose of the Study:

• To elucidate the structural basis of EcR-USP heterodimer DNA binding.
• To investigate the structural similarities between insect EcR-USP and mammalian EcR-RXR (retinoid X receptor) complexes.
• To provide a structural model for understanding FXR-RXR heterodimer binding to IR-1 sites.

Main Methods:

• X-ray crystallography was used to determine the structures of the EcR-USP and EcR-RXR DNA-binding domain (DBD) heterodimers bound to an IR-1 DNA element.
• The structures were solved at 2.24 Å (EcR-USP) and 2.60 Å (EcR-RXR) resolution.
• Sequence alignments were performed to compare receptor structures and infer functional relationships.

Main Results:

• The crystal structure of the EcR-USP DBD heterodimer bound to an idealized IR-1 element was determined.
• EcR and USP interact through similar surfaces, utilizing the deformed minor groove of the DNA for contact.
• The EcR-RXR DBD heterodimer shares the same dimerization and DNA-binding interfaces as the EcR-USP complex.

Conclusions:

• The EcR-USP heterodimer employs conserved structural mechanisms for DNA binding, involving protein-protein contacts mediated by the DNA minor groove.
• The EcR-RXR heterodimer serves as a relevant structural model for understanding the binding of other nuclear receptor heterodimers, such as FXR-RXR, to IR-1 sites.
• These findings enhance our understanding of nuclear receptor-mediated gene regulation in both insects and mammals.