SLC12A4/SLC12A6; A Target Enabling Package

KCC1 (SLC12A4) and KCC3 (SLC12A6) are co-transporters of potassium and chloride, and members of cation-chloride co-transporter (CCC; or Solute Carrier 12) family. They regulate chloride level and cell volume via export of potassium and chloride ions. KCC1 plays an important role in sickle cell diseases, where its activity leads to sickling of red blood cells, a key pathological feature of the disease. Hence, symptoms of this common genetic disorder can be significantly reduced by inactivation of KCC1. KCC3 is highly expressed in neurones, where its inherited defect can lead to a rare form of peripheral neuropathy, Andermann Syndrome. This TEP presents the structures of KCC1 and KCC3 in both wild-type and inactivated states, revealing structural mechanisms for their regulation. From these structures, we have identified ligands ATP and magnesium ion, and have subsequently used biophysical assay and mass spectrometry to characterise them. These can be exploited to develop small molecule modulators to treat sickle cell diseases, one of the most common genetic disorders with unmet needs, as well as neurological disorders.