Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Sequence specific assignment and determination of OSR1 C-terminal domain structure by NMR

AlAmri, Mubarak A., Jeeves, Mark and Mehellou, Youcef 2019. Sequence specific assignment and determination of OSR1 C-terminal domain structure by NMR. Biochemical and Biophysical Research Communications 512 (2) , pp. 338-343. 10.1016/j.bbrc.2019.03.065
Item availability restricted.

[img] PDF - Accepted Post-Print Version
Restricted to Repository staff only until 17 March 2020 due to copyright restrictions.

Download (3MB)

Abstract

The binding of SPAK and OSR1 kinases to their upstream WNK kinases is mediated by the interaction of their highly conserved SPAK and OSR1 C-terminal domain (CTD) to RFx [V/I] peptide sequences from WNK kinases. A SPAK CTD knock-in mouse, where SPAK was unable to bind WNK kinases, exhibited low blood pressure. This highlighted the inhibition of SPAK and OSR1 kinases binding to their upstream WNK kinases as a plausible strategy in the discovery of new antihypertensive agents. To facilitate such endeavour, we herein report the optimisation and expression of isotopically labelled OSR1 CTD in E.coli and a structural model based on the sequence specific NMR assignments giving insights into the structure of apo OSR1 CTD. Additionally, we identified the OSR1 CTD amino acid residues that are important for the binding of an 18-mer RFQV peptide derived from human WNK4. Collectively, the NMR backbone assignments and the generated OSR1 CTD 3D model reported in this work will be a powerful resource for the NMR-based discovery of small molecule OSR1 (and SPAK) kinase inhibitors as potential antihypertensive agents.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: Elsevier
ISSN: 0006-291X
Date of First Compliant Deposit: 27 March 2019
Date of Acceptance: 11 March 2019
Last Modified: 02 Jul 2019 17:49
URI: http://orca.cf.ac.uk/id/eprint/121232

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics