Y. Devedjiev et al., X-RAY STRUCTURE AT 1.76 ANGSTROM RESOLUTION OF A POLYPEPTIDE PHOSPHOLIPASE A(2) INHIBITOR, Journal of Molecular Biology, 266(1), 1997, pp. 160-172
The high resolution crystal structure of a natural PLA(2) inhibitor ha
s been determined by Patterson search methods. In the heterodimeric, n
eurotoxic complex, vipoxin, isolated from the venom of Bulgarian viper
, PLA(2) inhibitor represents the non-toxic subunit. The model was ref
ined to a crystallographic R-factor of 15.5% for data between 6 and 1.
76 Angstrom resolution. The packing of the inhibitor in the crystal re
veals close contacts between the molecules, which are symmetry-related
by the 2-fold axes of the lattice. These pairs associate as a crystal
lographic dimer, stabilized by a set of interactions, including van de
r Waals contacts between residues from symmetry-related pairs, denoted
as the recognition site and the recognition surface. Residues Ph3, Tr
p31 and Tyr119 represent the recognition site of inhibitor which possi
bly fits to the hydrophobic wall of the target PLA(2). The topology of
the inhibitor represents the PLA(2) type of folding: three long helic
es and a beta-hairpin. Superposition of the structure of the inhibitor
shows an almost complete overlap with different mammalian and viper P
LA(2) in the backbone and in the position of the sidechains of the res
idues that belong to the active centre and the hydrophobic wall. A ''l
ock and key'' mechanism of recognition of its native PLA(2) in gland c
ells and other toxic PLA(2) in vitro has been suggested. The mechanism
includes complementary ''head to tail'' interactions between the reco
gnition site of the inhibitor and a recognition surface located on the
hydrophobic wall of the target PLA(2). Having a high spatial homology
with the PLA(2) family of enzymes but opposing their action, the inhi
bitor from vipoxin presents an example of a divergent evolution of an
ancient PLA(2). The presence of a space for binding calcium in the inh
ibitor is believed to be a rudiment and proof of a common origin with
PLA(2). (C) 1997 Academic Press Limited.