1y4l
Crystal structure of Bothrops asper myotoxin II complexed with the anti-trypanosomal drug suramin
Structural highlights
FunctionPA2H2_BOTAS Snake venom phospholipase A2 homolog that lacks enzymatic activity. Is myotoxic and induces a dose-dependent edema in the mouse foot pad (PubMed:2781572, PubMed:9839670). Also exhibits strong anticoagulant effects by binding to factor Xa (F10) and inhibiting the prothrombinase activity (IC(50) is 3 nM) (PubMed:18062812). In addition, it shows cytotoxic activity to a variety of cell types and bactericidal activity to a variety of Gram-negative and Gram-positive bacteria (PubMed:7886694, PubMed:9654096, PubMed:9920486). Also induces a very rapid release of large amounts of potassium ions and ATP from muscle cells, which accounts for the pain reaction characteristic of viperid envenomations (PubMed:20660736). The released ATP amplifies the effect of the myotoxins, acting as a 'danger signal', which spreads and causes further damage by acting on purinergic receptors (PubMed:20660736). A model of myotoxic mechanism has been proposed: an apo Lys49-PLA2 is activated by the entrance of a hydrophobic molecule (e.g. fatty acid) at the hydrophobic channel of the protein leading to a reorientation of a monomer (By similarity). This reorientation causes a transition between 'inactive' to 'active' states, causing alignment of C-terminal and membrane-docking sites (MDoS) side-by-side and putting the membrane-disruption sites (MDiS) in the same plane, exposed to solvent and in a symmetric position for both monomers (By similarity). The MDoS region stabilizes the toxin on membrane by the interaction of charged residues with phospholipid head groups (By similarity). Subsequently, the MDiS region destabilizes the membrane with penetration of hydrophobic residues (By similarity). This insertion causes a disorganization of the membrane, allowing an uncontrolled influx of ions (i.e. calcium and sodium), and eventually triggering irreversible intracellular alterations and cell death (By similarity).[UniProtKB:I6L8L6][1] [2] [3] [4] [5] [6] [7] [8] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedSuramin, a synthetic polysulfonated compound, developed initially for the treatment of African trypanosomiasis and onchocerciasis, is currently used for the treatment of several medically relevant disorders. Suramin, heparin, and other polyanions inhibit the myotoxic activity of Lys49 phospholipase A2 analogues both in vitro and in vivo, and are thus of potential importance as therapeutic agents in the treatment of viperid snake bites. Due to its conformational flexibility around the single bonds that link the central phenyl rings to the secondary amide backbone, the symmetrical suramin molecule binds by an induced-fit mechanism complementing the hydrophobic surfaces of the dimer and adopts a novel conformation that lacks C2 symmetry in the dimeric crystal structure of the suramin-Bothrops asper myotoxin II complex. The simultaneous binding of suramin at the surfaces of the two monomers partially restricts access to the nominal active sites and significantly changes the overall charge of the interfacial recognition face of the protein, resulting in the inhibition of myotoxicity. Inhibition of myotoxic activity of Bothrops asper myotoxin II by the anti-trypanosomal drug suramin.,Murakami MT, Arruda EZ, Melo PA, Martinez AB, Calil-Elias S, Tomaz MA, Lomonte B, Gutierrez JM, Arni RK J Mol Biol. 2005 Jul 15;350(3):416-26. PMID:15961104[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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