1H-NMR assignments and secondary structure of dendroaspin, an RGD-containing glycoprotein IIb-IIIa (alpha IIb-beta 3) antagonist with a neurotoxin fold.
Dendroaspin, also referred to as mambin, was originally isolated from the venom of the Elapidae snake Dendroaspis jamesoni kaimose. It shares a high level of sequence similarity with the short-chain neurotoxins found in other Elapidae but displays approximately 1000-fold lower neurotoxin activity than the closely related protein erabutoxin b. However, unlike neurotoxins, it contains an RGD (Arg-Gly-Asp) motif and functions as an antagonist of platelet aggregation and cell-cell adhesion of comparable potency to the disintegrins from the venoms of Viperidae. We have determined the secondary structure of dendroaspin using 1H-NMR spectroscopy. Its structure resembles that of the short-chain neurotoxins, with three loops extending from a disulphide-bridged core; however, the strands of the triple-stranded beta-sheet are shorter and the loop containing the RGD sequence is moved away from this sheet. The structure bears little resemblance to that of the disintegrins, except in the RGD-containing loop, suggesting that this loop may be of prime importance in its inhibitory function. Comparison of this preliminary structure with that of the neurotoxins and disintegrins furthers our understanding of the mechanism of integrin antagonists and shows how the neurotoxin fold can be manipulated to give a variety of inhibitors.
Jaseja
M
M
School of Biochemistry, University of Birmingham, England.
Lu
X
X
Williams
J A
JA
Sutcliffe
M J
MJ
Kakkar
V V
VV
Parslow
R A
RA
Hyde
E I
EI
D000595:Amino Acid Sequence; D004546:Elapid Venoms / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000737:chemistry*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017421:Sequence Analysis; D014461:Ultracentrifugation
D004546:Elapid Venoms; D009498:Neurotoxins; D010980:Platelet Membrane Glycoproteins; C074772:mambin