Abstract
WNK kinases comprise a small group of unique serine/threonine protein kinases that have been genetically linked to pseudohypoaldosteronism type II, an autosomal dominant form of hypertension. Here we present the structure of the kinase domain of WNK1 at 1.8 Å resolution, solved in a low activity conformation. A lysine residue (Lys-233) is found in the active site emanating from strand β2 rather than strand β3 as in other protein kinases. The activation loop adopts a unique well-folded inactive conformation. The conformations of the P+1 specificity pocket, the placement of the conserved active site threonine (Thr-386), and the exterior placement of helix C, contribute to the low activity state. By homology modeling, we identified two hydrophobic residues in the substrate-binding groove that contribute to substrate specificity. The structure of the WNK1 catalytic domain, with its unique active site, may help in the design of therapeutic reagents for the treatment of hypertension.
| Original language | English |
|---|---|
| Pages (from-to) | 1303-1311 |
| Number of pages | 9 |
| Journal | Structure |
| Volume | 12 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 2004 |
Bibliographical note
Funding Information:We thank members of the Goldsmith lab for helpful discussions. We also thank Drs. Diana Tomchick and Mischa Machius and the staff at Argonne National Laboratory for help with Synchrotron data collection. We thank Dr. Dominika Borek for suggestions on data scaling. This research was supported by grants I1128 and I1143 from the Welch Foundation. Use of the Argonne National Laboratory Structural Biology Center beamlines at the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Biological and Environmental Research, under Contract No.W-31-109-ENG-38.