Human With No Lysine Kinase 3 (WNK3); A Target Enabling Package

Kinases WNK1-4 regulate cation-chloride cotransporters via phosphorylation of SPAK and OSR1 and thereby control salt homeostasis, cell volume and blood pressure. Gain of function mutations in WNK kinases are found in Gordon’s hypertension syndrome suggesting the WNK pathway as a therapeutic target. WNK3 inhibition in particular has also been shown to reduce cerebral injury after Ischemic stroke. Here we present assays and crystal structures that define (i) the molecular basis for disease mutations; (ii) the multiple functional domains of WNK kinases and their protein interactions; (iii) the binding of small molecule kinase inhibitors and a potential allosteric pocket.

WNK1-4激酶通过磷酸化SPAK和OSR1调控阳离子-氯离子协同转运蛋白，进而维持盐稳态、细胞体积与血压。WNK激酶的功能获得性突变可见于戈登氏高血压综合征（Gordon’s hypertension syndrome），提示WNK通路可作为潜在治疗靶点。另有研究表明，抑制WNK3可减轻缺血性脑卒中后的脑损伤。本研究呈现了一系列实验检测与晶体结构，阐明了以下三方面内容：(i) 疾病相关突变的分子基础；(ii) WNK激酶的多个功能结构域及其蛋白质相互作用；(iii) 小分子激酶抑制剂的结合特性与潜在变构口袋。