Ligandbinding Domain Variants

In the LBD, mutations collocate to (1) the "signature sequence," a conserved 20-amino acid region of NRs involved in ligand recognition and specificity;154 (2) AF-2, a binding site for the p160 cofactors; and (3) a region at the boundary of the hinge and LBD containing a 4-amino acid tetrapeptide (668QPIF671), which may define a protein-protein interaction surface (Fig. 16.5). Many of the AR gene mutations identified in the LBD of the AR in the TRAMP model, xenografts, and cell lines occur in the same three regions as mutations in clinical prostate cancer (Fig. 16.5). For example, a Phe-Ile671 mutation identified in an intact TRAMP mouse colocates to the 668qpiF671 tetrapeptide with mutations identified in human prostate cancer.8 Mutations of the AR gene identified in both clinical prostate cancer and TRAMP tumors in this region exhibit a two- to fourfold greater transactivation activity in response to DHT, nonclassical ligands, and hy-droxyflutamide compared to wtAR,8 without altering ligand-binding kinetics, receptor levels, or DNA-binding capacity. Homology modeling reveals that the 668QPIF671 tetrapeptide residues form a potential protein-protein interaction surface, which is markedly disrupted by the naturally occurring mutations, providing a mechanism that could explain the observed gain in transcriptional activity.8

Another AR missense mutation identified in the TRAMP model, Phe-Ser697, is located adjacent to the signature sequence. The Ser697 AR variant exhibits markedly reduced transactivation responses to progesterone and 17^-estradiol but enhanced response to R1881 compared to wtAR.152 These results are consistent with the role of the signature sequence in ligand recognition and specificity and with previous reports of mutations in this region in clinical disease.10,151 Analysis of the Thr-Ala877 AR variant, identified in a significant proportion of clinical prostate tumors and in the human prostate cancer cell line LNCaP has confirmed that this mutation exhibits increased transactivation activity in response to progesterone, 17^-estradiol, adrenal androgens, and hydroxyflutamide compared to wtAR.155 The recently determined AR LBD crystal struc-ture36,37 allowed us to use homology modeling to demonstrate that this mutation results in changes to the shape and volume of the ligand-binding pocket such that bulkier ligands like progesterone can be accommodated.152

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