A hotspot for posttranslational modifications on the androgen receptor dimer interface drives pathology and anti-androgen resistance.

Mutations of the androgen receptor (AR) associated with prostate cancer and androgen insensitivity syndrome may profoundly influence its structure, protein interaction network, and binding to chromatin, resulting in altered transcription signatures and drug responses. Current structural information fails to explain the effect of pathological mutations on AR structure-function relationship. Here, we have thoroughly studied the effects of selected mutations that span the complete dimer interface of AR ligand-binding domain (AR-LBD) using x-ray crystallography in combination with in vitro, in silico, and cell-based assays. We show that these variants alter AR-dependent transcription and responses to anti-androgens by inducing a previously undescribed allosteric switch in the AR-LBD that increases exposure of a major methylation target, Arg761. We also corroborate the relevance of residues Arg761 and Tyr764 for AR dimerization and function. Together, our results reveal allosteric coupling of AR dimerization and posttranslational modifications as a disease mechanism with implications for precision medicine.

Science advances. 2023 Mar 15 [Epub]

Andrea Alegre-Martí, Alba Jiménez-Panizo, Adrián Martínez-Tébar, Coralie Poulard, M Núria Peralta-Moreno, Montserrat Abella, Rosa Antón, Marcos Chiñas, Ulrich Eckhard, Josep M Piulats, Ana M Rojas, Juan Fernández-Recio, Jaime Rubio-Martínez, Muriel Le Romancer, Álvaro Aytes, Pablo Fuentes-Prior, Eva Estébanez-Perpiñá

Structural Biology of Nuclear Receptors, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona (UB), 08028 Barcelona, Spain., Programs of Molecular Mechanisms and Experimental Therapeutics in Oncology (ONCOBell) and Cancer Therapeutics Resistance (ProCURE), Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research, 08908 Barcelona, Spain., Cancer Research Center of Lyon, CNRS UMR5286, Inserm U1502, University of Lyon, 69000 Lyon, France., Department of Materials Science and Physical Chemistry, Faculty of Chemistry and Institut de Recerca en Química Teorica i Computacional (IQTCUB), 08028 Barcelona, Spain., Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain., Department of Structural and Molecular Biology, Molecular Biology Institute of Barcelona (IBMB-CSIC), 08028 Barcelona, Spain., Computational Biology and Bioinformatics, Andalusian Center for Developmental Biology (CABD-CSIC), 41013 Sevilla, Spain., Instituto de Ciencias de la Vid y del Vino (ICVV-CSIC), CSIC-UR-Gobierno de La Rioja, 26007 Logroño, Spain.