Abstract
Mutations of the p53-related protein kinase (PRPK) and TP53RK-binding protein (TPRKB) cause Galloway-Mowat syndrome (GAMOS) and are found in various human cancers. We have previously shown that small compounds targeting PRPK showed anti-cancer activity against colon and skin cancer. Here we present the 2.53 Å crystal structure of the human PRPK-TPRKB-AMPPNP (adenylyl-imidodiphosphate) complex. The structure reveals details in PRPK-AMPPNP coordination and PRPK-TPRKB interaction. PRPK appears in an active conformation, albeit lacking the conventional kinase activation loop. We constructed a structural model of the human EKC/KEOPS complex, composed of PRPK, TPRKB, OSGEP, LAGE3, and GON7. Disease mutations in PRPK and TPRKB are mapped into the structure, and we show that one mutation, PRPK K238Nfs*2, lost the binding to OSGEP. Our structure also makes the virtual screening possible and paves the way for more rational drug design.
Highlights
Mutations of the p53-related protein kinase (PRPK) and TP53RK-binding protein (TPRKB) cause Galloway-Mowat syndrome (GAMOS) and are found in various human cancers
We describe the crystal structure of human PRPK–TPRKB bound to AMPPNP at a resolution of 2.53 Å
In this study, we report the crystal structure of the human PRPK–TPRKB complex bound to AMPPNP
Summary
Mutations of the p53-related protein kinase (PRPK) and TP53RK-binding protein (TPRKB) cause Galloway-Mowat syndrome (GAMOS) and are found in various human cancers. We constructed a structural model of the human EKC/KEOPS complex, composed of PRPK, TPRKB, OSGEP, LAGE3, and GON7. Cgi[121] (TPRKB, TP53RK-binding protein), was identified by the same group through a yeast two-hybrid screen[2]. Beyond these studies, little is known about PRPK. A complex referred to as EKC/KEOPS (stands for endopeptidase-like kinase chromatin-associated/kinase, endopeptidase, and other proteins of small size) was identified as a telomere regulator[3] and a transcription complex[4] This complex is composed of Bud[32] (piD261, YGR262C), Cgi[121] (YML036W), Kae[1] (Ykr038c), Gon[7] (Yjl184w), and Pcc[1] (YKR095W). The human version of the KEOPS complex was finalized with the identification of C14ORF142 as the Gon[7] ortholog in human
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