Structural information is essential for a molecular understanding of protein function, and invaluable for basic and applied science. Nevertheless, such possibilities have remained unexploited for many targets due to the challenges associated with determination of protein structures. The overarching goal of this HALRIC pilot project is to elucidate molecular structural information of a physiologically‐relevant membrane protein in isolation or in complex with pharmacological compound candidates, as assessed in different cellular environments.

The focus will be on the ion homeostasis target ClC‐1 that is essential for human health and is a highly attractive target in the treatment of for example autoimmune and neuromuscular diseases (1). Recent structural breakthroughs by the Gourdon and Tidow laboratories at the Universities in Lund and Hamburg will be utilized synergistically with MAX IV and DESY, as well as ILL with the potential for future usage of the ESS.

The work will aim for a spatial understanding of the how the so‐called CBS domains orchestrate the ClC‐1 function via a phenomenon referred to as ‘slow‐gating’, thereby shedding light on the basic principles and determinants that govern ClC‐1. Focus will be using SAXS/SANS solution scattering to directly evaluate the conformational changes of the CBS domains, or to guide cryo‐EM experiments. Positive results have the potential to assist ongoing development of therapeutic intervention of severe disorders conducted by NMD Pharma in Aarhus, and to permit downstream similar initiatives to improve human health.

For further information about this HALRIC pilot project, please contact:

viktoria.baagenholm@sund.ku.dk
University of Copenhagen

pontus.gourdon@med.lu.se
Lund University

Reference:

1. Pedersen et al. Acta Physiologica 2021;233:e13690