5tf9
Crystal structure of WNK1 in complex with Mn2+AMPPNP and WNK476
Structural highlights
DiseaseWNK1_HUMAN Hereditary sensory and autonomic neuropathy type 2;Pseudohypoaldosteronism type 2C. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionWNK1_HUMAN Serine/threonine kinase which plays an important role in the regulation of electrolyte homeostasis, cell signaling, survival, and proliferation. Acts as an activator and inhibitor of sodium-coupled chloride cotransporters and potassium-coupled chloride cotransporters respectively. Activates SCNN1A, SCNN1B, SCNN1D and SGK1. Controls sodium and chloride ion transport by inhibiting the activity of WNK4, by either phosphorylating the kinase or via an interaction between WNK4 and the autoinhibitory domain of WNK1. WNK4 regulates the activity of the thiazide-sensitive Na-Cl cotransporter, SLC12A3, by phosphorylation. WNK1 may also play a role in actin cytoskeletal reorganization. Phosphorylates NEDD4L.[1] [2] Publication Abstract from PubMedProtein kinases are known for their highly conserved adenosine triphosphate (ATP)-binding site, rendering the discovery of selective inhibitors a major challenge. In theory, allosteric inhibitors can achieve high selectivity by targeting less conserved regions of the kinases, often with an added benefit of retaining efficacy under high physiological ATP concentration. Although often overlooked in favor of ATP-site directed approaches, performing a screen at high ATP concentration and/or stringent hit triaging with high ATP concentration offer conceptually simple methods of identifying allosteric inhibitors. Here we applied the latter approach to the With-No-Lysine (K) (WNK) kinases to discover lead molecules for a next-generation anti-hypertensive that requires a stringent safety profile. This strategy yielded several ATP non-competitive WNK1-4 kinase inhibitors, whose optimization enabled co-crystallization with WNK1, revealing an allosteric binding mode consistent with the observed exquisite specificity for WNK1-4 kinases. The optimized compound inhibited rubidium uptake by sodium chloride co-transporter 1 (NKCC1) in HT29 cells, consistent with the known WNK biology. Discovery and characterization of allosteric WNK kinase inhibitors.,Yamada K, Zhang JH, Xie X, Reinhardt J, Xie AQ, LaSala D, Kohls D, Yowe D, Burdick D, Yoshisue H, Wakai H, Schmidt I, Gunawan J, Yasoshima K, Yue QK, Kato M, Mogi M, Idamakanti N, Kreder N, Drueckes P, Pandey P, Kawanami T, Huang W, Yagi YI, Deng Z, Park HM ACS Chem Biol. 2016 Oct 7. PMID:27712055[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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