Crystallographic portrayal of different conformational states of a Lys49 phospholipase A₂ homologue: insights into structural determinants for myotoxicity and dimeric configuration

International Journal of Biological Macromolecules
A UllahRaghuvir K Arni

Abstract

Catalytically inactive phospholipase A(2) (PLA(2)) homologues play key roles in the pathogenesis induced by snake envenomation, causing extensive tissue damage via a mechanism still unknown. Although, the amino acid residues directly involved in catalysis are conserved, the substitution of Asp49 by Arg/Lys/Gln or Ser prevents the binding of the essential calcium ion and hence these proteins are incapable of hydrolyzing phospholipids. In this work, the crystal structure of a Lys49-PLA(2) homologue from Bothrops brazili (MTX-II) was solved in two conformational states: (a) native, with Lys49 singly coordinated by the backbone oxygen atom of Val31 and (b) complexed with tetraethylene glycol (TTEG). Interestingly, the TTEG molecule was observed in two different coordination cages depending on the orientation of the nominal calcium-binding loop and of the residue Lys49. These structural observations indicate a direct role for the residue Lys49 in the functioning of a catalytically inactive PLA(2) homologue suggesting a contribution of the active site-like region in the expression of pharmacological effects such as myotoxicity and edema formation. Despite the several crystal structures of Lys49-PLA(2) homologues already determined, t...Continue Reading

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Citations

Feb 23, 2019·Scientific Reports·Takashi MatsuiYoshikazu Tanaka
May 5, 2020·The Journal of Venomous Animals and Toxins Including Tropical Diseases·Libia SanzCleópatra A S Caldeira
Apr 27, 2013·Chemical Reviews·Artur GoraJiri Damborsky

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