1995
DOI: 10.1107/s0907444994011455
|View full text |Cite
|
Sign up to set email alerts
|

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

Abstract: 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 … Show more

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...
2
1

Citation Types

8
66
0
7

Year Published

1998
1998
2011
2011

Publication Types

Select...
8

Relationship

0
8

Authors

Journals

citations
Cited by 104 publications
(81 citation statements)
references
References 19 publications
8
66
0
7
Order By: Relevance
“…Initially Lys 49 -PLA 2 s were believed to be catalytically inactive because of flipping of the Cys 29 -Gly 30 peptide bond and their stereochemical incapacity to bind the cofactor calcium ion and thus stabilize the tetrahedral intermediate observed in the calcium-dependent catalytic reaction promoted by Asp 49 -PLA 2 s (31). This hypothesis was supported by structural analyses that have shown that the ⑀-amino group of Lys 49 is located in the position occupied by Ca 2ϩ in Asp 49 -PLA 2 (32)(33)(34). However, in vitro assays have provided evidence of a limited catalytic activity for Lys 49 -PLA 2 (35,36).…”
mentioning
confidence: 56%
See 2 more Smart Citations
“…Initially Lys 49 -PLA 2 s were believed to be catalytically inactive because of flipping of the Cys 29 -Gly 30 peptide bond and their stereochemical incapacity to bind the cofactor calcium ion and thus stabilize the tetrahedral intermediate observed in the calcium-dependent catalytic reaction promoted by Asp 49 -PLA 2 s (31). This hypothesis was supported by structural analyses that have shown that the ⑀-amino group of Lys 49 is located in the position occupied by Ca 2ϩ in Asp 49 -PLA 2 (32)(33)(34). However, in vitro assays have provided evidence of a limited catalytic activity for Lys 49 -PLA 2 (35,36).…”
mentioning
confidence: 56%
“…The sulfate ions in forms II and III are located in similar positions, ϳ6 Å closer to the active site than in form I (Fig. 1), and are bound by the side chains of Arg 34 , Lys 49 , Tyr 52 (not in form III due to a minor difference in the position of the sulfate), and Lys 53 . Significant differences exist in the side chain conformations of Lys 53 and Arg 34 in form I compared with the other two forms, in order to be able to interact with the anion at two distinct sites.…”
Section: Ligand-induced Conformational Change In Lys 49mentioning
confidence: 95%
See 1 more Smart Citation
“…Despite their catalytic inactivity, Lys49 PLA 2 s are very potent in the induction of myonecrosis, a major and clinically highly challenging event in envenomation by most viperid snakes, based on one or more mechanisms that continue to be enigmatic to toxinologists. Consequently, a number of different strategies, such as structural analysis (Arni & Ward, 1996;Ownby et al, 1999;Murakami & Arni, 2003), chemical modification (Andriã o-Escarso et al, 2000;Soares et al, 2001), sequence-comparison analyses (Selistre de Araujo et al, 1996;Ward et al, 1998), charge-distribution analysis (Kini & Iwanaga, 1986;Kini & Evans, 1989), hydrophobicity profiles (Kini & Iwanaga, 1986), synthetic peptide studies (Lomonte et al, 1994;Nuñ ez et al, 2001) and site-directed mutagenesis (Ward et al, 2002), have attempted to elucidate the structural determinants for the myotoxicity expressed by Lys49 PLA 2 s. The three-dimensional structures of a large number of Lys49 PLA 2 s in both native and complexed states have recently been elucidated (Arni et al, 1995;Lee et al, 2001;Ambrosio et al, 2005;Murakami et al, 2005Murakami et al, , 2006Murakami et al, , 2007 and have contributed to addressing the role of Lys122 in the myotoxicity of Lys49 PLA 2 s (Ambrosio et al, 2005;Watanabe et al, 2005).…”
Section: Introductionmentioning
confidence: 99%
“…The enzymatically inactive PLA 2 s (K-49 PLA 2 , PLA 2 -like myotoxins) are PLA 2 s which exhibit low or no phospholipid cleavage activity. This is thought to arise from a substitution of the aspartate residue at position 49, the side chain of which is important in the binding of calcium ions (an essential cofactor), by a lysine residue (Holland et al, 1990;Scott et al, 1992;Arni et al, 1995). However, despite the low or lack of enzymatic activity, K-49 PLA 2 s exhibits several different pharmacological activities, such as post-synaptic neurotoxicity, oedema formation (Gutie  rrez & Lomonte, 1995), myotoxicity (Lomonte et al, 1994) and liposome and membrane disruption (Dõ Âas et al, 1991;Ruf®ni et al, 1992).…”
Section: Introductionmentioning
confidence: 99%