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Crystal structure of a myotoxic Asp49-phospholipase A 2 with low catalytic activity: Insights into Ca 2+ -independent catalytic mechanism

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, ISSN: 1570-9639, Vol: 1784, Issue: 4, Page: 591-599
2008
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A myotoxic Asp49-phospholipase A 2 (Asp49-PLA 2 ) with low catalytic activity (BthTX-II from Bothrops jararacussu venom) was crystallized and the molecular-replacement solution has been obtained with a dimer in the asymmetric unit. The quaternary structure of BthTX-II resembles the myotoxic Asp49-PLA 2 PrTX-III (piratoxin III from B. pirajai venom) and all non-catalytic and myotoxic dimeric Lys49-PLA 2 s. Despite of this, BthTX-II is different from the highly catalytic and non-myotoxic BthA-I (acidic PLA 2 from B. jararacussu ) and other Asp49-PLA 2 s. BthTX-II structure showed a severe distortion of calcium-binding loop leading to displacement of the C-terminal region. Tyr28 side chain, present in this region, is in an opposite position in relation to the same residue in the catalytic activity Asp49-PLA 2 s, making a hydrogen bond with the atom Oδ2 of the catalytically active Asp49, which should coordinate the calcium. This high distortion may also be confirmed by the inability of BthTX-II to bind Na + ions at the Ca 2+ -binding loop, despite of the crystallization to have occurred in the presence of this ion. In contrast, other Asp49-PLA 2 s which are able to bind Ca 2+ ions are also able to bind Na + ions at this loop. The comparison with other catalytic, non-catalytic and inhibited PLA 2 s indicates that the BthTX-II is not able to bind calcium ions; consequently, we suggest that its low catalytic function is based on an alternative way compared with other PLA 2 s.

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