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Crystal structure of human RIOK2 bound to a specific inhibitor

DOI: 10.1098/rsob.190037 DOI Help

Authors: Jing Wang (Structural Genomics Consortium, University of Oxford) , Thibault Varin (Eli Lilly and Company) , Michal Vieth (Eli Lilly and Company) , Jonathan M. Elkins (Structural Genomics Consortium, University of Oxford; Cidade Universitária Zeferino Vaz)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Open Biology , VOL 9

State: Published (Approved)
Published: April 2019

Open Access Open Access

Abstract: The RIO kinases (RIOKs) are a universal family of atypical kinases that are essential for assembly of the pre-40S ribosome complex. Here, we present the crystal structure of human RIO kinase 2 (RIOK2) bound to a specific inhibitor. This first crystal structure of an inhibitor-bound RIO kinase reveals the binding mode of the inhibitor and explains the structure–activity relationship of the inhibitor series. The inhibitor binds in the ATP-binding site and forms extensive hydrophobic interactions with residues at the entrance to the ATP-binding site. Analysis of the conservation of active site residues reveals the reasons for the specificity of the inhibitor for RIOK2 over RIOK1 and RIOK3, and it provides a template for inhibitor design against the human RIOK family.

Journal Keywords: ribosome assembly; RIOK2; 40s; inhibitor; RIO kinase; crystal structure

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I02-Macromolecular Crystallography

Documents:
nj4j4.pdf