2XEG: Human Glutamate Carboxypeptidase Ii In Complex With Antibody-Recruiting Molecule Arm-P4

Citation:
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.
PDB ID: 2XEGDownload
MMDB ID: 84625
PDB Deposition Date: 2010/5/14
Updated in MMDB: 2010/11
Experimental Method:
x-ray diffraction
Resolution: 1.59  Å
Source Organism:
Similar Structures:
Biological Unit for 2XEG: dimeric; determined by author and by software (PISA)
Molecular Components in 2XEG
Label Count Molecule
Proteins (2 molecules)
2
Glutamate Carboxypeptidase 2(Gene symbol: FOLH1)
Molecule annotation
Chemicals (30 molecules)
1
4
2
2
3
2
4
20
5
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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