1clp
From Proteopedia
CRYSTAL STRUCTURE OF A CALCIUM-INDEPENDENT PHOSPHOLIPASELIKE MYOTOXIC PROTEIN FROM BOTHROPS ASPER VENOM
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 PubMedMyotoxin II, a myotoxic calcium-independent phospholipase-like protein isolated from the venom of Bothrops asper, possesses no detectable phospholipase activity. The crystal structure has been determined and refined at 2.8 A to an R-factor of 16.5% (F > 3sigma) with excellent stereochemistry. Amino-acid differences between catalytically active phospholipases and myotoxin II in the Ca(2+)-binding region, specifically the substitutions Tyr28-->Asn, Gly32-->Leu and Asp49-->Lys, result in an altered local conformation. The key difference is that the epsilon-amino group of Lys49 fills the site normally occupied by the calcium ion in catalytically active phospholipases. In contrast to the homologous monomeric Lys49 variant from Agkistrodon piscivorus piscivorus, myotoxin II is present as a dimer both in solution and in the crystalline state. The two molecules in the asymmetric unit are related by a nearly perfect twofold axis, yet the dimer is radically different from the dimer formed by the phospholipase from Crotalus atrox. Whereas in C. atrox the dimer interface occludes the active sites, in myotoxin II they are exposed to solvent. Structure of a calcium-independent phospholipase-like myotoxic protein from Bothrops asper venom.,Arni RK, Ward RJ, Gutierrez JM, Tulinsky A Acta Crystallogr D Biol Crystallogr. 1995 May 1;51(Pt 3):311-7. PMID:15299297[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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