Snake venom contains a number of the hemostatically active C-type lectin-like
proteins, which affect the interaction between von Willebrand factor (vWF) and
the platelet glycoprotein (GP) Ib or platelet receptor to inhibit/induce
platelet activation. Flavocetin-A (FL-A) is a high-molecular mass C-type
lectin-like protein (149 kDa) isolated from the habu snake venom. FL-A binds
with high affinity to the platelet GP Ibalpha-subunit and functions as a strong
inhibitor of vWF-dependent platelet aggregation. We have determined the X-ray
crystal structure of FL-A and refined to 2.5 A resolution. This is a first
elucidation of a three-dimensional structure of the platelet GP Ib-binding
protein. The overall structure reveals that the molecule is a novel cyclic
tetramer (alphabeta)(4) made up of four alphabeta-heterodimers related by a
crystallographic 4-fold symmetry. The tetramerization is mediated by an
interchain disulfide bridge between cysteine residues at the C-terminus of the
alpha-subunit and at the N-terminus of the beta-subunit in the neighboring
alphabeta-heterodimer. The high affinity of FL-A for the platelet GP Ib
alpha-subunit could be explained by a cooperative-binding action through the
multiple binding sites of the tetramer.
