title: Crystal structures of human prostatic acid phosphatase in complex with a phosphate ion and alpha-benzylaminobenzylphosphonic acid update the mechanistic picture and offer new insights into inhibitor design.
abstract: The X-ray crystal structure of human prostatic acid phosphatase (PAP) in complex with a phosphate ion has been determined at 2.4 A resolution. This structure offers a snapshot of the final intermediate in the catalytic mechanism and does not support the role of Asp 258 as a proton donor in catalysis. A total of eight hydrogen bonds serve to strongly bind the phosphate ion within the active site. Bound PEG molecules from the crystallization matrix have allowed the identification of a channel within the molecule that likely plays a role in molecular recognition and in macromolecular substrate selectivity. Additionally, the structure of PAP in complex with a phosphate derivative, alpha-benzylaminobenzylphosphonic acid, a potent inhibitor (IC(50) = 4 nM), has been determined to 2.9 A resolution. This structure gives new insight into the determinants of binding hydrophobic ligands within the active site and allows us to explain PAP's preference for aromatic substrates.
authors.affiliation: Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Ortlund
authors.forename: Michael W
authors.initials: MW
authors.lastname: LaCount
authors.forename: Lukasz
authors.initials: L
authors.lastname: Lebioda
mesh_terms: D000135:Acid Phosphatase; D000818:Animals; D001665:Binding Sites; D002241:Carbohydrates / Q000737:chemistry; D002384:Catalysis; D018360:Crystallography, X-Ray; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006801:Humans; D046911:Macromolecular Substances; D008297:Male; D008956:Models, Chemical; D008958:Models, Molecular; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry*; D010710:Phosphates / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D051381:Rats; D012661:Semen / Q000201:enzymology
chemical_list: D002241:Carbohydrates; D004791:Enzyme Inhibitors; D046911:Macromolecular Substances; D063065:Organophosphonates; D010710:Phosphates; C472310:alpha-benzylaminobenzylphosphonic acid; D011092:Polyethylene Glycols; D000135:Acid Phosphatase; C428439:prostatic acid phosphatase; D017027:Protein Tyrosine Phosphatases