A team led by researchers of the Institute of Biomedicine of the University of Barcelona (IBUB) and the Research Institute of the Hospital de la Santa Creu i Sant Pau (IIB Sant Pau) shows for the first time, the three-dimensional structure of the homodimeric androgen receptor ligand-binding domain, a structure that eluded researchers for years. This new structure of the nuclear receptor allows explaining more than forty mutations related to prostate cancer, one of the most common worldwide and especially in Catalonia, as well as known developing disorders such as the androgen insensitivity syndromes.
The research has been co-directed by Eva Estébanez Perpiñá, IBUB researcher and Serra Hunter professor, together with Pablo Fuentes Prior researcher from IBB-Sant Pau, both members of the Research Group Bases Estructurals de Processos Fisiopatològics Fonamentals, recognized by the Generalitat de Catalunya, and from the Xarxa Nacional de Receptors Nuclears (National Network of Nuclear Receptors) from the Ministry of Economy, Industry and Competitiveness.
The human androgen receptor is a key protein in the regular development and activity of the prostate in response to male hormones such as testosterone.. The deregulating activity of the receptor is directly related to the carcinogenesis of the prostate gland. Therefore, "the resolution of its three-dimensional structure is an essential key to diagnose and predict prostate cancer, as well as monitoring patient's resistance to medicine", says Eva Estébanez Perpiñá.
The androgenic receptor was and still is the central target of the fight against prostate cancer. Identifying its homodimeric three-dimensional structure suggests new therapeutic strategies. "Actually, we started exploring the design of a new generation of drugs in collaboration with pharmaceutical companies in order to step forward towards a precision medicine for the prostate cancer", says Estébanez Perpiñá.
This work, published in Nature Communications, enables understanding the molecular bases of mutations detected in patients of prostate cancer and also in the ones with androgenic insensitivity syndrome (AIS), a disease caused by the mutations in the X chromosome that create a resistance to male hormones.
New generation of drugs to treat prostate cancer
At this moment, prostate cancer is the most common malignant tumour among men from industrialized countries. In Catalonia, the number of cases has grown dramatically over the last years, and studies show that more than 30.000 people will be diagnosed with this neoplasia by 2020. The main difficulties to treat this pathology are, on the one hand, the high clinical heterogeneity and, on the other, the quick appearance of resistance to used drugs. So far, treatments have focused on known compounds such as antiandrogens, which act on the androgenic receptor and stop the male sexual hormones action..
The three-dimensional structure presented in this work provides ways of allosteric communication between the functional areas of the binding domain in the androgens -that is, between the elements of the receptor which are in indirect physical contact- and which are essential for the regular and pathological functioning of the nuclear receptor. "These interconnections, identified in the dimeric form of the receptor suggest a complexity of activity which is much bigger than what we thought so far, and with a direct impact on the drug design that can remove secondary effects caused by the current used drugs", says Fuentes Prior.
The researchers show for the first time in high resolution (2,15 angstroms) the dimeric structure of the binding domain in human androgen receptor hormones, and they prove this structure is essential for the biological activity of this important nuclear receptor. "The new drugs to be developed out of this discovery -adds Fuentes Prior- will block the physiopathological processes coming from the union of these hormones, instead of competing with the union of natural hormones -like current antiandrogens do", concluded the researcher.
The research, signed by Marta Nadal (IBUB) as its first co-author, counts with the participation of Marta Taulés, researcher of the Scientific and Technological Centers of the UB, and the team of Marta Vilaseca, researcher of the Institute for Research in Biomedicine, both centers located at the Barcelona Science Park (PCB), apart from two researchers from the team of Professor Franck Claessens (Univesity of Leuven, Belgium) and the researchers Adriaan Houtsmuller and Martin van Royen (Erasmus University Rotterdam, Netherlands).