A remote arene-binding site on prostate specific membrane antigen revealed by antibody-recruiting small molecules.
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.
Zhang
Andrew X
AX
Department of Chemistry, Yale University, 225 Prospect Street, P.O. Box 208107, New Haven, Connecticut 06510-8107, USA.
Murelli
Ryan P
RP
Barinka
Cyril
C
Michel
Julien
J
Cocleaza
Alexandra
A
Jorgensen
William L
WL
Lubkowski
Jacek
J
Spiegel
David A
DA
D000906:Antibodies / Q000737:chemistry* / Q000276:immunology; D000937:Antigen-Antibody Reactions; D001665:Binding Sites; D006801:Humans; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D017430:Prostate-Specific Antigen / Q000737:chemistry* / Q000276:immunology; D011471:Prostatic Neoplasms / Q000737:chemistry* / Q000175:diagnosis / Q000276:immunology; D012680:Sensitivity and Specificity
D000906:Antibodies; D017430:Prostate-Specific Antigen