SLC12A4/SLC12A6; A Target Enabling Package
Creators
- Gamma Chi1
- Rebecca Ebenhoch1
- Henry Man1
- Haiping Tang2
- Laurence E. Tremblay3
- Gabriella Reggiano4
- Xingyu Qiu2
- Tina Bohstedt1
- Patrizia Abrusci1
- Ben Tehan5
- Idlir Liko5
- Fernando Almeida5
- Alexandre P. Garneau6
- Dong Wang1
- Gavin McKinley1
- Shubhashish M.M. Mukhopadhyay1
- Alejandra Fernandez-Cid1
- Samira Slimani3
- , Julie L. Lavoie6
- Nicola Burgess-Brown1
- Frank DiMaio4
- Paul Isenring3
- Carol V. Robinson2
- Katharina L. Duerr1
- 1. Structural Genomics Consortium
- 2. Physical and Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, Oxford
- 3. Department of Medicine, Nephrology Research Group, Faculty of Medicine, Laval University, Quebec City, Québec, Canada
- 4. Department of Biochemistry, University of Washington, 1705 NE Pacific St, Seattle, 98195, Washington, USA
- 5. Omass Therapeutics, The Schrödinger Building, Heatley Road, Oxford Science Park, Oxford, OX4 4GE, UK
- 6. Cardiometabolic Axis, School of Kinesiology and Physical Activity Sciences, University of Montréal, Montréal, Quebec, Canada
Description
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.
Notes
Files
SLC12A4 SLC12A6 TEP_v1.pdf
Files
(1.8 MB)
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Additional details
Related works
- Is part of
- https://www.thesgc.org/tep (URL)
Funding
- A UK Hub to Catalyse Open Target Discovery. 106169
- Wellcome Trust