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Structural mechanism underlying variations in DNA binding by the androgen receptor

DOI: 10.1016/j.jsbmb.2024.106499 DOI Help

Authors: Xiao Yin Lee (KU Leuven) , Wout Van Eynde (KU Leuven) , Christine Helsen (KU Leuven) , Hanne Willems (KU Leuven) , Kaat Peperstraete (KU Leuven) , Sofie De Block (KU Leuven) , Arnout Voet (KU Leuven) , Frank Claessens (KU Leuven)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Journal Of Steroid Biochemistry And Molecular Biology , VOL 241

State: Published (Approved)
Published: July 2024
Diamond Proposal Number(s): 19190

Open Access Open Access

Abstract: The androgen receptor (AR) is a steroid activated transcription factor which recognizes DNA motifs resembling inverted repeats of a conserved 5’-AGAACA-3’-like hexanucleotides separated by a three-nucleotide spacer from a similar, but less conserved hexanucleotide. Here, we report the structures of the human AR DNA binding domain (DBD) bound to two natural AREs (C3 and MTV) in head-to-head dimer conformations, diffracting at 2.05 Å and 2.25 Å, respectively. These structures help to explain the impact of androgen insensitivity mutations on the structure integrity, DNA binding and DBD dimerization. The binding affinity of the AR DBD to different DNA motifs were measured by the BioLayer Interferometry (BLI) and further validated by Molecular Dynamics (MD) simulations. This shows that the high binding affinity of the first DBD to the upstream 5’-AGAACA-3’ motif induces the cooperative binding of the second DBD to the second hexanucleotide. Our data indicate identical interaction of the DBDs to the upstream hexanucleotides, while forming an induced closer contact of the second DBD on the non-canonical hexanucleotides. The variation in binding between the DBD monomers are the result of differences in DNA occupancy, protein-protein interactions, DNA binding affinity, and DNA binding energy profiles. We propose this has functional consequences.

Journal Keywords: Androgen receptor; Androgen response element; DNA-binding domain; Crystal structure; X-ray crystallography; Molecular Dynamics simulation

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I24-Microfocus Macromolecular Crystallography

Other Facilities: ID23–2 at ESRF

Added On: 15/04/2024 09:10

Documents:
1-s2.0-S0960076024000475-main.pdf

Discipline Tags:

Biochemistry Genetics Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)