Crystal structures of SERCA in complex with inhibitors with potential as prostate cancer drugs

Abstract

Casein kinase ll (CK2) is a serine/threonine kinase and widely distributed in various tissues. CK2 predominantly exists in the form of heterotetramer composed of two catalytic subunits (CK2alpha or CK2alpha prime) and two regulatory subunits (CK2beta). Recently, the CK2alpha inhibition has been revealed to prevent the progression of glomerulonephritis. On the other hand, inhibition of CK2alpha prime in testis affect the spermatogenesis. In order to develop of novel CK2 inhibitor for nephritis, we determined the first structure of CK2alpha prime complexed with a potent inhibitor and compared with the structure of CK2alpha. The crystal structure of a C-terminal deletion mutant of human Ck2alpha prime was solved and refined to 3.2 Å resolution. Two isozymes, CK2alpha and CK2alpha prime, reveal the high similarity of the overall structure. The largest structural difference between CK2alpha prime and human Ck2alpha occurs at the loop connecting the strands beta 4 and beta 5. The corresponding region belongs on one hand to the CK2alpha/ CK2beta interface in the holoenzyme and on the other hand to the catalytic core, which is structurally highly conserved among the eukaryotic protein kinases. This observation is consistent with the growing evidence that CK2alpha prime and CK2alpha may possess the difference of the relation in vivo with CK2beta and the substrate recognition.