Myotoxin II from Bothrops asper (terciopelo) venom is a lysine-49 phospholipase A2

Francis, Brian R.; Gutiérrez, José Marı́a; Lomonte, Bruno; Kaiser, Ivan I.

doi:10.1016/0003-9861(91)90307-5

Cited by 191 publications

(104 citation statements)

References 44 publications

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“…Recently, a sub-class of snake-venom PLA2-1ike proteins which retain cytotoxicity, but lack phospholipase activity have been identified and sequenced (Maraganore et al, 1984;Maraganore, Poorman & Heinrickson, 1987;Yoshizumi et al, 1990;Liu et al, 1990;Homsi-Brandenburgo, Queiroz, Santo-Neto, Rodrigues-Simon & Giglio, 1988;Francis, Gutierrez, Lomonte & Kaiser, 1991). In the catalytically active PLA2, calcium is an essential co-factor, and the noncatalytic PLA2-1ike proteins are primarily characterized by the substitution of Asp49 by Lys.…”

Section: Introductionmentioning

confidence: 99%

Structure of a calcium-independent phospholipase-like myotoxic protein fromBothrops aspervenom

Arni¹,

Ward²,

Gutiérrez³

et al. 1995

Acta Crystallogr D Biol Crystallogr

104

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Myotoxin 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 2.8A to an R factor of 16.5% (F>3o') with excellent stereochemistry. Amino-acid differences between catalytically active phospholipases and myotoxin II in the Ca2+-binding region, specifically the substitutions Tyr28~Asn, Gly32~Leu and Asp49~Lys, result in an altered local conformation. The key difference is that the e-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.

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Section: Introductionmentioning

confidence: 99%

Structure of a calcium-independent phospholipase-like myotoxic protein fromBothrops aspervenom

Arni¹,

Ward²,

Gutiérrez³

et al. 1995

Acta Crystallogr D Biol Crystallogr

104

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“…Despite having little or no enzymatic activity, Lys 49 -PLA 2 s are very active in induction of myonecrosis (16,40,41).…”

mentioning

confidence: 99%

A Molecular Mechanism for Lys49-Phospholipase A2 Activity Based on Ligand-induced Conformational Change

Ambrósio

Nonato²,

Araújo

et al. 2005

Journal of Biological Chemistry

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Agkistrodon contortrix laticinctus myotoxin is a Lys49 -phospholipase A 2 (EC 3.1.1.4) isolated from the venom of the serpent A. contortrix laticinctus (broad-banded copperhead). We present here three monomeric crystal structures of the myotoxin, obtained under different crystallization conditions. The three forms present notable structural differences and reveal that the presence of a ligand in the active site (naturally presumed to be a fatty acid) induces the exposure of a hydrophobic surface (the hydrophobic knuckle) toward the C terminus. The knuckle in A. contortrix laticinctus myotoxin involves the side chains of Phe 121 and Phe 124 and is a consequence of the formation of a canonical structure for the main chain within the region of residues 118 -125. Comparison with other Lys49 -phospholipase A 2 myotoxins shows that although the knuckle is a generic structural motif common to all members of the family, it is not readily recognizable by simple sequence analyses. An activation mechanism is proposed that relates fatty acid retention at the active site to conformational changes within the C-terminal region, a part of the molecule that has long been associated with Ca 2؉ -independent membrane damaging activity and myotoxicity. This provides, for the first time, a direct structural connection between the phospholipase "active site" and the C-terminal "myotoxic site," justifying the otherwise enigmatic conservation of the residues of the former in supposedly catalytically inactive molecules.

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“…Accurate atomic resolution crystal structures are required to answer questions concerning the possible structural basis for these biological functions. According to conventional wisdom, the catalytic activity of PLA2s depends on the binding of a calcium ion and on the presence of residue Asp 49 (4). (The conventional numbering system of Renetseder et al (5) is used throughout this report.)…”

mentioning

confidence: 99%

The Crystal Structure of a Novel, Inactive, Lysine 49 PLA2 from Agkistrodon acutus Venom

Liu

Huang

Teng

et al. 2003

Journal of Biological Chemistry

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The crystal structure of acutohaemolysin, a lysine 49 phospholipase A2 protein with 1010 non-hydrogen protein atoms and 232 water molecules, has been determined ab initio using the program SnB at an ultrahigh resolution of 0.8 Å. The lack of catalytic activity appears to be related to the presence of Phe 102 , which prevents the access of substrate to the active site. The substitution of tryptophan for leucine at residue 10 interferes with dimer formation and may be responsible for the additional loss of hemolytic activity. The ultrahigh resolution of the experimental diffraction data permits alternative conformations to be modeled for disordered residues, many hydrogen atoms to be located, the protonation of the N⑀2 atom in the catalytic residue His 48 to be observed experimentally, and the density of the bonding electrons to be analyzed in detail.

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Myotoxin II from Bothrops asper (terciopelo) venom is a lysine-49 phospholipase A2

Cited by 191 publications

References 44 publications

Structure of a calcium-independent phospholipase-like myotoxic protein fromBothrops aspervenom

Structure of a calcium-independent phospholipase-like myotoxic protein fromBothrops aspervenom

A Molecular Mechanism for Lys49-Phospholipase A2 Activity Based on Ligand-induced Conformational Change

The Crystal Structure of a Novel, Inactive, Lysine 49 PLA2 from Agkistrodon acutus Venom

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