Structural characterization of the PSMA/Glu-490 complex
a Molecular formula of the Glu-490. b A stereo view of the Gluo-490 inhibitor. The Fo-Fc omit map (green) is contoured at 3.0 σ and the inhibitor is shown in stick representation with atoms colored red (oxygen), blue (nitrogen), yellow (sulfur), and cyan (carbon). c Details of interactions between residues of the glutarate sensor (green carbons) and Glu-490 (cyan carbons). CH–π interactions are depicted as dashed lines with distances to the ring centers in Angstroms. The active-site zinc ions are shown as orange spheres. d Surface representation of PSMA with residues of the glutarate sensor interaction with the FMR moiety colored blue, PDB code (7BFZ).
Surgery is an efficient way to treat localized prostate cancer (PCa), however, it is challenging to demarcate rapidly and accurately the tumor boundary intraoperatively, as existing tumor detection methods are seldom performed in real-time. To overcome those limitations, we develop a fluorescent molecular rotor that specifically targets the prostate-specific membrane antigen (PSMA), an established marker for PCa. The probes have picomolar affinity (IC50 = 63-118 pM) for PSMA and generate virtually instantaneous onset of robust fluorescent signal proportional to the concentration of the PSMA-probe complex. In vitro and ex vivo experiments using PCa cell lines and clinical samples, respectively, indicate the utility of the probe for biomedical applications, including real-time monitoring of endocytosis and tumor staging. Experiments performed in a PCa xenograft model reveal suitability of the probe for imaging applications in vivo.
Zhang, J.; Rakhimbekova, A.; Duan, X.; Yin, Q.; Foss, C. A.; Fan, Y.; Xu, Y.; Li, X.; Cai, X.; Kutil, Z.; Wang., P.; Yang, Z.; Zhang, N.; Pomper, M. G.; Wang, Y.; Bařinka, C. & Yang, X.: A prostate-specific membrane antigen activated molecular rotor for real-time fluorescence imaging, Nature Commun. (2021)12:5460, https://doi.org/10.1038/s41467-021-25746-6