ArticleScientific reports2019
Comparative structural and evolutionary analyses predict functional sites in the artemisinin resistance malaria protein K13.
Article in Scientific reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 2 of them syntheses that pooled it.
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Who cites it
23 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Ubiquitin-proteasome system inFrontiers in medicine · 2024Pooled it
- Identification of Co-Existing Mutations and Gene Expression Trends Associated With K13-Mediated Artemisinin Resistance inFrontiers in genetics · 2022Pooled it
- Divergent Autophagy Pathways in Plasmodium: Mechanisms, Functions, and Therapeutic Potential.Molecular microbiology · 2026Review
- Stabilizing Plasmodium falciparum proteins for small molecule drug discovery.Protein science : a publication of the Protein Society · 2026Article
- Role of novel mutations in food vacuole transporters beyond K13-mediated artemisinin resistance inAntimicrobial agents and chemotherapy · 2025Article
- NovelAntimicrobial agents and chemotherapy · 2025Article
- Polymorphisms in Pfkelch13 domains before and after the introduction of artemisinin-based combination therapy in Southwest Nigeria.PloS one · 2025Article
- Artemisinin-resistant Plasmodium falciparum Kelch13 mutant proteins display reduced heme-binding affinity and decreased artemisinin activation.Communications biology · 2024Article
- An overview of artemisinin-resistant malaria and associated Pfk13 gene mutations in Central Africa.Parasitology research · 2024Review
- Evaluation of Dihydroartemisinin-Piperaquine Efficacy and Molecular Markers in Uncomplicated Falciparum Patients: A Study across Binh Phuoc and Dak Nong, Vietnam.Medicina (Kaunas, Lithuania) · 2024Article
- Evaluation of the binding interactions between Plasmodium falciparum Kelch-13 mutant recombinant proteins with artemisinin.PloS one · 2024Article
- Screening for K13-Propeller Mutations Associated with Artemisinin Resistance in Plasmodium falciparum in Yambio County (Western Equatoria State, South Sudan).The American journal of tropical medicine and hygiene · 2023Article
- Ex vivo RSA and pfkelch13 targeted-amplicon deep sequencing reveal parasites susceptibility to artemisinin in Senegal, 2017.Malaria journal · 2023Article
- Regulation of Cell Proliferation and Nrf2-Mediated Antioxidant Defense: Conservation of Keap1 Cysteines and Nrf2 Binding Site in the Context of the Evolution of KLHL Family.Life (Basel, Switzerland) · 2023Article
- A Plasmodium falciparum RING Finger E3 Ubiquitin Ligase Modifies the Roles of PfMDR1 and PfCRT in Parasite Drug Responses.Antimicrobial agents and chemotherapy · 2023Article
- Ex vivo RSA and Pfkelch13 targeted-amplicon deep sequencing reveal parasites susceptibility to artemisinin in Senegal, 2017.Research square · 2023Article
- Structural Modelling Prediction of RecombinantPathogens (Basel, Switzerland) · 2022Article
- Article
- Mutation in the Plasmodium falciparum BTB/POZ Domain of K13 Protein Confers Artemisinin Resistance.Antimicrobial agents and chemotherapy · 2022Article
- Plasmodium falciparum resistance to ACTs: Emergence, mechanisms, and outlook.International journal for parasitology. Drugs and drug resistance · 2021Article
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Authors and funding
5 authors.
Funding
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Abstract
Numerous mutations in the Plasmodium falciparum Kelch13 (K13) protein confer resistance to artemisinin derivatives, the current front-line antimalarial drugs. K13 is an essential protein that contains BTB and Kelch-repeat propeller (KREP) domains usually found in E3 ubiquitin ligase complexes that target substrate protein(s) for ubiquitin-dependent degradation. K13 is thought to bind substrate proteins, but its functional/interaction sites and the structural alterations associated with artemisinin resistance mutations remain unknown. Here, we screened for the most evolutionarily conserved sites in the protein structure of K13 as indicators of structural and/or functional constraints. We inferred structure-dependent substitution rates at each amino acid site of the highly conserved K13 protein during the evolution of Apicomplexa parasites. We found two solvent-exposed patches of extraordinarily conserved sites likely involved in protein-protein interactions, one in BTB and the other one in KREP. The conserved patch in K13 KREP overlaps with a shallow pocket that displays a differential electrostatic surface potential, relative to neighboring sites, and that is rich in serine and arginine residues. Comparative structural and evolutionary analyses revealed that these properties were also found in the functionally-validated shallow pocket of other KREPs including that of the cancer-related KEAP1 protein. Finally, molecular dynamics simulations carried out on PfK13 R539T and C580Y artemisinin resistance mutant structures revealed some local structural destabilization of KREP but not in its shallow pocket. These findings open new avenues of research on one of the most enigmatic malaria proteins with the utmost clinical importance.
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