Structural model of human PSA: a target for prostate cancer therapy

Abstract

Based on unique biology of prostate cancer, prostate-specific antigen could be a useful target for prostate cancer therapies. Such targeting requires the identification of highly selective inhibitor-binding sites. Three-dimensional structure was calculated by homology modeling. The overall structure of human prostate-specific antigen is composed of two β-barrel domain, kallikrein loop and active-site triad His⁵⁷, Asp¹⁰², and Ser¹⁹⁵. Structure of human prostate-specific antigen is quite similar to hK-1 and HPK-3. The major differences were observed at kallikrein loop and position of active site. The substrate-binding pocket is predominated by hydrophobic residues and the bottom of the specificity pocket contains Ser¹⁸⁹ as in chymotrypsin, which provides substrate specificity. The hydrophobic, and preferentially aromatic (Trp215), amino acid residues are determinant of substrate binding due to the presence of hydrophobic crevice between Tyr⁹⁹ and Trp²¹⁵. Crystal structure of human prostate-specific antigen is not determined till now and hence the report on an accurate and comparative model of human prostate-specific antigen is probably to help in understanding their functional network and finally could be helpful in structure-based rational drug designing.