Crystal structure of the human PRPK-TPRKB complex.

Area of Science:

• Biochemistry
• Structural Biology
• Genetics

Background:

• Mutations in p53-related protein kinase (PRPK) and TP53RK-binding protein (TPRKB) are implicated in Galloway-Mowat syndrome (GAMOS) and human cancers.
• Previous research demonstrated anti-cancer activity of small compounds targeting PRPK against colon and skin cancer.

Purpose of the Study:

• To elucidate the structural basis of PRPK-TPRKB interaction and PRPK-AMPPNP coordination.
• To model the human EKC/KEOPS complex and map disease-associated mutations.
• To provide a structural foundation for rational drug design targeting PRPK.

Main Methods:

• X-ray crystallography of the human PRPK-TPRKB-AMPPNP complex at 2.53 Å resolution.
• Construction of a structural model for the human EKC/KEOPS complex.
• Mapping of disease mutations onto the structural model.

Main Results:

• The crystal structure reveals detailed PRPK-AMPPNP coordination and PRPK-TPRKB interactions.
• PRPK adopts an active conformation despite lacking a conventional kinase activation loop.
• A disease mutation (PRPK K238Nfs*2) was shown to disrupt PRPK binding to OSGEP within the EKC/KEOPS complex.

Conclusions:

• The determined structure provides insights into the functional mechanisms of PRPK and its role in disease.
• The structural model of the EKC/KEOPS complex aids in understanding the impact of mutations.
• This work facilitates virtual screening and the development of targeted therapeutics for PRPK-related disorders and cancers.