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Structure of the OSR1 kinase, a hypertension drug target
Author(s) -
Villa Fabrizio,
Deak Maria,
Alessi Dario R.,
van Aalten Daan M. F.
Publication year - 2008
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.22238
Subject(s) - drug , pharmacology , kinase , chemistry , computational biology , medicine , biology , biochemistry
The oxidative stress-responsive kinase-1 (OSR1) and STE20/SPS1-related proline/alanine-rich kinase (SPAK) interact, phosphorylate, and stimulate the activity of the cation-chloride cotransporters (NKCC1, NKCC2, and the Na1:Cl2 cotransporter (NCC)).1–4 These cotransporters play key roles in regulating salt intake and secretion from cells (reviewed in Refs. 5,6). Some of the most commonly prescribed blood pressure-lowering thiazide drugs exert their physiological effects by inhibiting NCC. The SPAK and OSR1 enzymes are phosphorylated and activated by the WNK1 and WNK4 protein kinases in response to hyperosmotic and hypotonic stress.7–9 This may increase blood pressure by stimulating phosphorylation and activation of NCC.3 Consistent with this, WNK1 and WNK4 genes are mutated in patients suffering from an inherited hypertension and hyperkalemia (elevated plasma K) disorder, termed pseudohypoaldosteronism type II.10,11 SPAK and OSR1 are 68% identical in sequence and possess a highly similar kinase catalytic domain as well as a conserved C-terminal (CCT) domain.4 The CCT domain operates as a docking site enabling OSR1 and SPAK to interact with RFXV (Arg-Phe-Xaa-Val) motifs found in both their upstream activators as well as their substrates.2,12,13 Structural analysis revealed that the CCT domain forms a novel protein fold.14 The WNK1 and WNK4 protein kinases phosphorylate OSR1 and SPAK at their T-loop residue within the kinase catalytic domain (Thr185 in OSR1, Thr233 in SPAK).9 It is possible that inhibition of the WNK/OSR1/NCC phosphorylation cascade with kinase inhibitors may provide an alternative chemotherapeutic approach to direct inhibition of NCC. As a first step towards this, we describe the first crystal structure of an OSR1 fragment encompassing the catalytic domain of the enzyme.