This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Our goal is to determine the crystal structures of both apo Wnk and in complex with a series of inhibitors derived from our proprietary scaffold discovery platform. WnK is serine-threonine kinase and linked to pseudohypoaldosteronism type 2, also known as Gordon hyperkalemia-hypertension syndrome, which is a rare autosomal dominant form of volume-dependent, low-renin hypertension characterized by hyperkalemia and hyperchloremic acidosis with normal glomerular filtration. This proposed experiment will lead to a new structure of a very important family of serine-threonine kinase as well as many co-complex structures of Wnk with inhibitors. Some of those proprietary compounds are of novel scaffolds against both serine/threonine and tyrosine kinases. These structures will enable us to understand the mode of interaction of those novel scaffolds. Those novel scaffolds could serve as the basis of the iterative design of Wnk inhibitors and could lead to a drug that can be used to treat the Gordon hyperkalemia-hypertension syndrome.
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