The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA.
Northeastern Collaborative Access Team, Argonne National Laboratory, Argonne, IL, 60439, USA.
Commun Biol. 2021 Feb 5;4(1):167. doi: 10.1038/s42003-021-01683-4.
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.
p53 相关蛋白激酶（PRPK）和 TP53RK 结合蛋白（TPRKB）的突变导致 Galloway-Mowat 综合征（GAMOS），并存在于各种人类癌症中。我们之前已经表明，针对 PRPK 的小分子化合物对结肠癌和皮肤癌具有抗癌活性。在这里，我们展示了人 PRPK-TPRKB-AMPPNP（腺苷酰基-亚氨基二磷酸）复合物的 2.53Å 晶体结构。该结构揭示了 PRPK-AMPPNP 协调和 PRPK-TPRKB 相互作用的细节。PRPK 呈现出活跃的构象，尽管缺乏传统的激酶激活环。我们构建了由 PRPK、TPRKB、OSGEP、LAGE3 和 GON7 组成的人 EKC/KEOPS 复合物的结构模型。PRPK 和 TPRKB 的疾病突变映射到结构中，我们表明一个突变，PRPK K238Nfs*2，失去了与 OSGEP 的结合。我们的结构还使得虚拟筛选成为可能，并为更合理的药物设计铺平了道路。
