4k09
From Proteopedia
Crystal structure of BbTX-II from Bothrops brazili venom
Structural highlights
FunctionPA2H1_BOTBZ Snake venom phospholipase A2 homolog that lacks enzymatic activity. Is myotoxic and displays edema-inducing activities in mouse paw (PubMed:18602430). Also displays cytotoxic activity against some cell lines, and antimicrobial activities against E.coli, C.albicans and Leishmania (PubMed:18602430). 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 (PubMed:24145104). 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 (PubMed:24145104). The MDoS region stabilizes the toxin on membrane by the interaction of charged residues with phospholipid head groups (PubMed:24145104). Subsequently, the MDiS region destabilizes the membrane with penetration of hydrophobic residues (PubMed:24145104). 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 (PubMed:24145104).[1] [2] Publication Abstract from PubMedBothrops brazili is a snake found in the forests of the Amazonian region whose commercial therapeutic anti-bothropic serum has low efficacy for local myotoxic effects, resulting in an important public health problem in this area. Catalytically inactive phospholipases A2-like (Lys49-PLA2s) are among the main components from Bothrops genus venoms and are capable of causing drastic myonecrosis. Several studies have shown that the C-terminal region of these toxins, which includes a variable combination of positively charged and hydrophobic residues, is responsible for their activity. In this work we describe the crystal structures of two Lys49-PLA2s (BbTX-II and MTX-II) from B. brazili venom and a comprehensive structural comparison with several Lys49-PLA2s. Based on these results, two independent sites of interaction were identified between protein and membrane which leads to the proposition of a new myotoxic mechanism for bothropic Lys49-PLA2s composed of five different steps. This proposition is able to fully explain the action of these toxins and may be useful to develop efficient inhibitors to complement the conventional antivenom administration. Structural bases for a complete myotoxic mechanism: Crystal structures of two non-catalytic phospholipases A-like from Bothrops brazili venom.,Fernandes CA, Comparetti EJ, Borges RJ, Huancahuire-Vega S, Ponce-Soto LA, Marangoni S, Soares AM, Fontes MR Biochim Biophys Acta. 2013 Oct 18;1834(12):2772-2781. doi:, 10.1016/j.bbapap.2013.10.009. PMID:24145104[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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