2ok9 | pdb_00002ok9
PrTX-I-BPB
Structural highlights
Function[PA2H1_BOTPI] Snake venom phospholipase A2 (PLA2) homolog that lacks enzymatic activity, but displays myotoxin and edema-inducing activities in vivo. In vitro neuromuscular activities have also been observed, but they are not found in vivo and can be explained by the destabilization of the muscle membrane by the toxin. The myotoxic activity is inhibited by rosmarinic acid (RA).[1] [2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedFor the first time, the structure of a catalytic inactive phospholipase A(2) homolog (Lys49-PLA(2)s) complexed with p-bromophenacyl bromide (BPB) has been solved by X-ray crystallography. Lys49-PLA(2)s are among the main components of Viperidae snake venoms, causing myonecrosis and other actions despite their catalytic inactivity. BPB, a classic inhibitor of catalytic-active PLA(2)s, has been used since the 1970s because it binds specifically the His48 residue of the catalytic site. Curiously, when Lys49-PLA(2) is chemically modified by BPB, it causes a partial inhibition of the myotoxic function which is associated with the C-terminus and not with the catalytic site. The structure of PrTX-I complexed to BPB revealed unambiguously that the inhibitor binds covalently to His48, causing a distortion of the Ca(2)(+)-binding loop region and C-terminus rearrangement in one of its monomers. The comparison between the apo and BPB-complexed PrTX-I structures showed an increased symmetry between the two monomers with the formation of an interchain hydrogen bond between Tyr119 residues. PrTX-I undergoes tertiary and quaternary structural changes when complexed to BPB which could be related to reduction of myotoxicity and other toxic activities. We also proposed a novel myotoxic inhibition hypothesis integrating "myotoxic" and "active" sites for bothropic Lys49-PLA(2)s. Crystal structure of a phospholipase A(2) homolog complexed with p-bromophenacyl bromide reveals important structural changes associated with the inhibition of myotoxic activity.,Marchi-Salvador DP, Fernandes CA, Silveira LB, Soares AM, Fontes MR Biochim Biophys Acta. 2009 Nov;1794(11):1583-90. Epub 2009 Jul 16. PMID:19616648[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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