Structural mapping of Kelch13 mutations associated with artemisinin resistance in malaria

Mutations in Plasmodium falciparum gene kelch13 (pfkelch13) are strongly and causally associated with resistance to anti-malarial drug artemisinin, but their effects on PfKelch13 structure and function remain unclear. Utilizing the publicly available three-dimensional structure of PfKech13 (PDB ID: 4yy8), we find that most of the mutations in its propeller domain occur in two spatial clusters. Of these, one cluster is enriched in surface exposed residues which may drive PfKelch13-centered protein interactions, and the second cluster mostly contains residues which are buried and whose mutations may destabilize PfKelch13 structure. The most prevalent resistant mutations C580Y and Y493H are distal from the above two clusters. The C580Y mutation creates sterically unfavourable contacts while Y493H possibly alters the hydrophobic core of the propeller domain. These analyses will facilitate further experimental studies aimed at understanding how mutations in pfkelch13 lead to artemisinin resistance.