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

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.

• Authors: Andrew X Zhang, Ryan P Murelli, Cyril Barinka, Julien Michel, Alexandra Cocleaza, William L Jorgensen, Jacek Lubkowski, David A Spiegel
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 132 Issue 36 Pg. 12711-6 (Sep 15 2010) ISSN: 1520-5126 [Electronic] United States
• PMID: 20726553 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antibodies
• Prostate-Specific Antigen

Topics

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