Structure Activity Relationship (SAR)
The natural occurring α-LTX dimer has to form a tetramer to be toxic. Tetramerisation occurs only in the presence of bivalent cations (such as Ca2+ or Mg2+) or amphipathic molecules. The four monomers that form this tetramer are symmetrically arranged around a central axis, resembling a four-blade propeller with a diameter of 250 Å and a thickness of 100 Å. The head domains form the compact, central mass brought together and surrounded by the body domains. The wings stand perpendicular towards the axis of the tetramer. Because of this form the tetramer contains a pear-shaped channel in the central mass. At the lower end the diameter of this channel is 25Å, then widens to 36 Å to be constricted to 10 Å at the top.
The base of the tetramer (below the wings) is 45Å deep and is hydrophobic which mediates insertion into the cell membrane. Also insertion of the tetramer is only possible in presence of certain receptors (mainly neurexin Iα and latrophilin and PTPσ in a minor extent) on the membrane. Neurexin Iα only mediates insertion under presence of Ca2+, whereas latrophilin and PTPσ can mediate insertion without presence of Ca2+. So because of the channel and the insertion in the cell membrane the protein makes the cell more permeable to substances that can pass through the channel. These substances are mono- and bivalent cations, neurotransmitters, fluoscent dyes and ATP.
Read more about this topic: Alpha-Latrotoxin
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