Human 5'-NT und P2X receptors: Structure, function and inhibitor design
Zusammenfassung der Projektergebnisse
In this project we could determine the first crystal structure of CD73, an interesting pharmaceutical target for cancer immunotherapy. The protein structure was characterised in the open and closed conformation and in complex with the nucleotide derivative AMPCP, yielding insight into the domain motion and catalysis of the enzyme. Furthermore, we supported the development of tight binding CD73 inhibitors in cooperation with the group of Christa Müller (Bonn) by determining co-crystal structures with a number of synthetic inhibitors. The expression of P2X receptor ectodomains in functional form was unfortunately not successful. The crystal structure of the full-length P2X4 receptor suggested that the ectodomains might fold and associate to homotrimers also in the absence of the transmembrane domain, but all trials of expression in E. coli and HEK293 cells only yielded misfolded or aggregated protein or very low expression yields. Further work should concentrate on the expression of full-length protein. In addition to CD73, we could crystallize NPP3, another ectoenzyme involved in purinergic signalling.
Projektbezogene Publikationen (Auswahl)
- Cellular function and molecular structure of ectonucleotidases. Purinergic Signal. 2012; 8: 437-502
Zimmermann H, Zebisch M, Sträter N
(Siehe online unter https://doi.org/10.1007/s11302-012-9309-4) - Crystal structure of the human ecto-5'-nucleotidase (CD73): insights into the regulation of purinergic signaling. Structure 2012; 20: 2161-73
Knapp K, Zebisch M, Pippel J, El-Tayeb A, Müller CE, Sträter N
(Siehe online unter https://doi.org/10.1016/j.str.2012.10.001) - Crystallization and preliminary X-ray analysis of the open form of human ecto-5'-nucleotidase (CD73). Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012; 68: 1545-9
Knapp KM, Zebisch M, Sträter N
(Siehe online unter https://doi.org/10.1107/S1744309112045447)
