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Cancer Center, The Burnham Institute, La Jolla, California 92037 [S. M., L. B., K. R. E.], and Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [D. B. A., H. I. S.]
Androgen receptors (ARs) belong to the family of hormone receptors that
are ligand-dependent transcription factors. Endocrine therapy provides
effective treatment for prostate cancer until mutations arise that
alter the ligand responsiveness of AR. In this study, structural models
were developed for the functional domains of human AR by homology
modeling from crystal structures of closely related nuclear receptors.
These models were used to locate the sites of two frequently occurring
mutations in prostate cancer. The substitutions that develop in LNCaP
(threonine
alanine at residue 877) and CWR22 (histidinetyrosine at
residue 874) tumor cell lines are both located on helix 11 that forms
part of the ligand-binding pocket. However, the results suggest that
these mutations influence ligand responsiveness by completely different
mechanisms. Residue 877 contacts the ligand directly, and substitution
at this site alters the stereochemistry of the binding pocket. Thus,
the LNCaP mutation apparently broadens the specificity of ligand
recognition. In contrast, residue 874 is located down the helical axis,
projects away from the ligand pocket, and does not contact ligand. The
side chain of residue 874 lies in a cavity between helices 11 and 12.
Substitution of tyrosine for histidine 874 in CWR22 tumors may affect a
conformational change of helix 12 and, thus, influence binding of
coactivator proteins and their regulatory effect on transcriptional
activation.
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