Mambin, a potent glycoprotein IIb-IIIa antagonist and platelet aggregation inhibitor structurally related to the short neurotoxins.
The purification, complete amino acid sequence, functional activity, and structural modeling are described for mambin, a platelet glycoprotein GP IIb-IIIa antagonist and potent inhibitor of platelet aggregation from the venom of the Elapidae snake Dendroaspis jamesonii (Jameson's mamba). Mambin is 59 residues in length and contains four disulfide linkages and an RGD amino acid sequence found in protein ligands that bind to GP IIb-IIIa. Mambin inhibits ADP-induced platelet aggregation (IC50 = 172 +/- 22 nM) and inhibits the binding of purified platelet fibrinogen receptor GP IIb-IIIa to immobilized fibrinogen (IC50 = 3.1 +/- 0.8 nM). Mambin has very little sequence similarity to the Viperidae family of platelet aggregation inhibitors, except for the RGD-containing region in the protein. However, mambin does have ca. 47% similarity to the short-chain postsynaptic neurotoxins found in other Elapidae venoms, which do not contain the RGD sequence and do not act as GP IIb-IIIa antagonists. On the basis of its circular dichroism spectrum, mambin has a beta-sheet structure characteristic of the neurotoxins. Molecular modeling of the mambin sequence onto the erabutoxin b structure predicts a very similar structure within the entire protein except for the loop containing the RGD sequence. Mambin may therefore represent a genetic hybrid of neurotoxic and hemotoxic proteins found in snake venoms.
McDowell
R S
RS
Department of Bioorganic Chemistry, Genentech, Inc., South San Francisco, California 94080.
Dennis
M S
MS
Louie
A
A
Shuster
M
M
Mulkerrin
M G
MG
Lazarus
R A
RA
D000595:Amino Acid Sequence; D004546:Elapid Venoms; D006801:Humans; D013058:Mass Spectrometry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000737:chemistry*; D018733:Nicotinic Antagonists; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D011487:Protein Conformation; D011506:Proteins / Q000302:isolation & purification / Q000494:pharmacology*; D016415:Sequence Alignment
D004546:Elapid Venoms; D009498:Neurotoxins; D018733:Nicotinic Antagonists; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D011506:Proteins; C074772:mambin