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Crystal structure of the D49 phospholipase A2 piratoxin III from Bothrops pirajai.
Structural highlights
FunctionPA2H3_BOTPI Snake venom phospholipase A2 (PLA2) that lacks enzymatic activity. Shows high myotoxin activities (PubMed:10395455). Also has anticoagulant activity (PubMed:10395455). 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] 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 PubMedSnake venoms are rich sources of phospholipase A(2) homologues, both active calcium-binding Asp49 enzymes and essentially inactive Lys49 proteins. They are responsible for multiple pharmacological effects, some of which are dependent on catalytic activity and others of which are not. Here, the 2.4 A X-ray crystal structure of an active Asp49 phospholipase A(2) from the venom of the snake Bothrops pirajai, refined to conventional and free R values of 20.1 and 25.5%, respectively, is reported. Unusually for phospholipases A(2), the dependence of the enzyme rate on the substrate concentration is sigmoidal, implying cooperativity of substrate binding. The unprecedented structural distortion seen for the calcium-binding loop in the present structure may therefore be indicative of a T-state enzyme. An explanation of the interaction between the substrate-binding sites based on the canonical phospholipase A(2) dimer is difficult. However, an alternative putative dimer interface identified in the crystal lattice brings together the calcium-binding loops of neighbouring molecules, along with the C-terminal regions which are disulfide bonded to those loops, thereby offering a possible route of communication between active sites. The structure of the D49 phospholipase A2 piratoxin III from Bothrops pirajai reveals unprecedented structural displacement of the calcium-binding loop: possiblerelationship to cooperative substrate binding.,Rigden DJ, Hwa LW, Marangoni S, Toyama MH, Polikarpov I Acta Crystallogr D Biol Crystallogr. 2003 Feb;59(Pt 2):255-62. Epub 2003, Jan 23. PMID:12554936[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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