X-ray structure at 1.76 Å resolution of a polypeptide phospholipase A2 Inhibitor 1 1 Edited by R. Huber

Devedjiev, Y.; Попов, А. Н.; Атанасов, Б.; Bartunik, H.D.

doi:10.1006/jmbi.1996.0778

Cited by 22 publications

(11 citation statements)

References 44 publications

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“…One of the most striking features of the vipoxin complex is the manner in which the complex is formed. The reported structures of PLA 2 from Crotalus atrox , and recently the structure of the isolated inhibitor of vipoxin [17]show that both form dimers with an almost exact two‐fold rotational symmetry. Based on this arrangement Devedjiew et al [17]have proposed a model for the vipoxin complex with a similar complex conformation.…”

Section: Resultsmentioning

confidence: 99%

Crystal structure of vipoxin at 2.0 Å: an example of regulation of a toxic function generated by molecular evolution

Perbandt

Wilson

Eschenburg³

et al. 1997

FEBS Letters

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Vipoxin is the main toxic component in the venom of the Bulgarian snake Vipera ammodytes meridionalis, the most toxic snake in Europe. Vipoxin is a complex between a toxic phospholipase A 2 (PLA 2 ) and a non-toxic protein inhibitor. The structure is of genetic interest due to the high degree of sequence homology (62%) between the two functionally different components. The structure shows that the formation of the complex in vipoxin is significantly different to that seen in many known structures of phospholipases and contradicts the assumptions made in earlier studies. The modulation of PLA 2 activity is of great pharmacological interest, and the present structure will be a model for structure-based drug design.

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Section: Resultsmentioning

confidence: 99%

Crystal structure of vipoxin at 2.0 Å: an example of regulation of a toxic function generated by molecular evolution

Perbandt

Wilson

Eschenburg³

et al. 1997

FEBS Letters

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“…The presence of inactive enzyme homologues is widespread in many enzyme families and they have often acquired functions in regulatory networks, co-evolving with increasing cellular and organismal complexity (Bartlett et al 2003). A mechanistic explanation could be the shift from substrate catalysis to substrate binding only (Devedjiev et al 1997;Lamb et al 2000). It has been argued that nonenzyme proteins are derived from catalytic precursors, because the majority of members of a particular enzyme family are active (Todd et al 2002).…”

Section: Characterization Of Novel Members Of the Calpain Superfamilymentioning

confidence: 99%

Evolutionary Relationships and Protein Domain Architecture in an Expanded Calpain Superfamily in Kinetoplastid Parasites

2005

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Abstract. Employing whole-genome analysis we have characterized a large family of genes coding for calpain-related proteins in three kinetoplastid parasites. We have defined a total of 18 calpain-like sequences in Trypanosoma brucei, 27 in Leishmania major, and 24 in Trypanosoma cruzi. Sequence characterization revealed a well-conserved protease domain in most proteins, although residues critical for catalytic activity were frequently altered. Many of the proteins contain a novel N-terminal sequence motif unique to kinetoplastids. Furthermore, 24 of the sequences contain N-terminal fatty acid acylation motifs indicating association of these proteins with intracellular membranes. This extended family of proteins also includes a group of sequences that completely lack a protease domain but is specifically related to other kinetoplastid calpain-related proteins by a highly conserved N-terminal domain and by genomic organization. All sequences lack the C-terminal calmodulin-related calcium-binding domain typical of most mammalian calpains. Our analysis emphasizes the highly modular structure of calpains and calpain-like proteins, suggesting that they are involved in diverse cellular functions. The discovery of this surprisingly large family of calpain-like proteins in lower eukaryotes that combines novel and conserved sequence modules contributes to our understanding of the evolution of this abundant protein family.

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“…The conformation is mainly supported by the ionic interaction of the Inh Lys 69 toward Asp 49 of the PLA 2 , distorting the Ca 2 + -binding region and, furthermore, the carbonyl oxygens of the potential calcium-binding ligands Tyr 28 and Gly 32 are turned away to be involved in intermolecular H bonds. The crystallographic structure of Inh has been published [61], and it shows almost the same homodimeric conformation as found for other snake PLA 2 homodimers, demonstrating that vipoxin is a unique complex.…”

Section: Vipoxin: a Unique Example Of Modulation Of The Toxic Functiomentioning

confidence: 67%

Modulation of phospholipase A 2 activity generated by molecular evolution

Betzel

Genov

Rajashankar

et al. 1999

Cellular and Molecular Life Sciences (CMLS)

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Snake venom oligomeric neurotoxins offer several unique examples of modulation of phospholipase A2 (PLA2) activity generated by molecular evolution. This phenomenon was found in evolutionary younger snakes and is probably common for representatives of the genus Vipera. At present, the best-studied example is the heterodimeric neurotoxin vipoxin from the venom of the southeast European snake Vipera ammodytes meridionalis. It is a complex between a basic strongly toxic PLA2 and an acidic and catalytically inactive PLA2-like component (Inh). This is the first reported example of a high degree of structural homology (62%) between an enzyme and its natural protein inhibitor. The inhibitor is a product of the divergent evolution of the unstable PLA2 in order to stabilize it and to preserve the pharmacological activity/toxicity for a long time. Inh reduces both the catalytic activity and toxicity of PLA2. Vipoxin also illustrates evolution of the catalytic into a inhibitory function. Vipoxin analogues have been found in the venom of viperid snakes inhabiting diverse regions of the world. An attempt is made to explain modulation of the toxic function by the three-dimensional structure of vipoxin.

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X-ray structure at 1.76 Å resolution of a polypeptide phospholipase A2 Inhibitor 1 1 Edited by R. Huber

Cited by 22 publications

References 44 publications

Crystal structure of vipoxin at 2.0 Å: an example of regulation of a toxic function generated by molecular evolution

Crystal structure of vipoxin at 2.0 Å: an example of regulation of a toxic function generated by molecular evolution

Evolutionary Relationships and Protein Domain Architecture in an Expanded Calpain Superfamily in Kinetoplastid Parasites

Modulation of phospholipase A 2 activity generated by molecular evolution

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