A remote arene-binding site on prostate specific membrane antigen revealed by antibody-recruiting small molecules

J Am Chem Soc. 2010 Sep 15;132(36):12711-6. doi: 10.1021/ja104591m.

Abstract

Prostate specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase overexpressed in many forms of prostate cancer. Our laboratory has recently disclosed a class of small molecules, called ARM-Ps (antibody-recruiting molecule targeting prostate cancer) that are capable of enhancing antibody-mediated immune recognition of prostate cancer cells. Interestingly, during the course of these studies, we found ARM-Ps to exhibit extraordinarily high potencies toward PSMA, compared to previously reported inhibitors. Here, we report in-depth biochemical, crystallographic, and computational investigations which elucidate the origin of the observed affinity enhancement. These studies reveal a previously unreported arene-binding site on PSMA, which we believe participates in an aromatic stacking interaction with ARMs. Although this site is composed of only a few amino acid residues, it drastically enhances small molecule binding affinity. These results provide critical insights into the design of PSMA-targeted small molecules for prostate cancer diagnosis and treatment; more broadly, the presence of similar arene-binding sites throughout the proteome could prove widely enabling in the optimization of small molecule-protein interactions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antibodies / chemistry*
  • Antibodies / immunology
  • Antigen-Antibody Reactions
  • Binding Sites
  • Humans
  • Male
  • Models, Molecular
  • Molecular Structure
  • Molecular Weight
  • Prostate-Specific Antigen / chemistry*
  • Prostate-Specific Antigen / immunology
  • Prostatic Neoplasms / chemistry*
  • Prostatic Neoplasms / diagnosis
  • Prostatic Neoplasms / immunology
  • Sensitivity and Specificity

Substances

  • Antibodies
  • Prostate-Specific Antigen