ArticleProceedings of the National Academy of Sciences of the United States of America2012
Unique thrombin inhibition mechanism by anophelin, an anticoagulant from the malaria vector.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- Structural basis for the procoagulant activity ofBiological chemistry · 2026Review
- Beyond the bite: how mosquito salivary proteins modulate midgut biology and malaria parasite transmission.Current opinion in insect science · 2025Review
- Prospection of Peptide Inhibitors of Thrombin from Diverse Origins Using a Machine Learning Pipeline.Bioengineering (Basel, Switzerland) · 2023Article
- A mosquito AgTRIO mRNA vaccine contributes to immunity against malaria.NPJ vaccines · 2023Article
- Mosquito Salivary Proteins and Arbovirus Infection: From Viral Enhancers to Potential Targets for Vaccines.Pathogens (Basel, Switzerland) · 2023Review
- A toolbox of engineered mosquito lines to study salivary gland biology and malaria transmission.PLoS pathogens · 2022Article
- Novel Inhibitors and Activity-Based Probes Targeting Trypsin-Like Serine Proteases.Frontiers in chemistry · 2022Article
- Screening of the Promising Direct Thrombin Inhibitors from Haematophagous Organisms. Part I: Recombinant Analogues and Their Antithrombotic Activity In Vitro.Biomedicines · 2021Article
- Insects as Diet and Therapy: Perspectives on Their Use for Combating Diabetes Mellitus in Tanzania.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Efficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors.Nature communications · 2021Article
- Mast Cells and Basophils in the Defense against Ectoparasites: Efficient Degradation of Parasite Anticoagulants by the Connective Tissue Mast Cell Chymases.International journal of molecular sciences · 2021Article
- Exosite Binding in Thrombin: A Global Structural/Dynamic Overview of Complexes with Aptamers and Other Ligands.International journal of molecular sciences · 2021Review
- The Effects of A Mosquito Salivary Protein on Sporozoite Traversal of Host Cells.The Journal of infectious diseases · 2021Article
- Article
- Rapid assembly and profiling of an anticoagulant sulfoprotein library.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- An insight into the sialotranscriptome and virome of Amazonian anophelines.BMC genomics · 2019Article
- An unexpected switch in peptide binding mode: from simulation to substrate specificity.Journal of biomolecular structure & dynamics · 2018Article
- Mosquito-Derived Anophelin Sulfoproteins Are Potent Antithrombotics.ACS central science · 2018Article
- Comprehensive review of methods for prediction of intrinsic disorder and its molecular functions.Cellular and molecular life sciences : CMLS · 2017Review
- Tyrosine sulfation modulates activity of tick-derived thrombin inhibitors.Nature chemistry · 2017Article
Corrections and comments
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Authors and funding
7 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Anopheles mosquitoes are vectors of malaria, a potentially fatal blood disease affecting half a billion humans worldwide. These blood-feeding insects include in their antihemostatic arsenal a potent thrombin inhibitor, the flexible and cysteine-less anophelin. Here, we present a thorough structure-and-function analysis of thrombin inhibition by anophelin, including the 2.3-Å crystal structure of the human thrombin·anophelin complex. Anophelin residues 32-61 are well-defined by electron density, completely occupying the long cleft between the active site and exosite I. However, in striking contrast to substrates, the D50-R53 anophelin tetrapeptide occupies the active site cleft of the enzyme, whereas the upstream residues A35-P45 shield the regulatory exosite I, defining a unique reverse-binding mode of an inhibitor to the target proteinase. The extensive interactions established, the disruption of thrombin's active site charge-relay system, and the insertion of residue R53 into the proteinase S(1) pocket in an orientation opposed to productive substrates explain anophelin's remarkable specificity and resistance to proteolysis by thrombin. Complementary biophysical and functional characterization of point mutants and truncated versions of anophelin unambiguously establish the molecular mechanism of action of this family of serine proteinase inhibitors (I77). These findings have implications for the design of novel antithrombotics.
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