1993, English, Article edition: Strong inhibition of fibrinogen binding to platelet receptor {alpha}IIb{beta}3 by RGD sequences installed into a presentation scaffold Lee, Grace; Chan, Winnie; Hurle, Mark R.; ...

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Physical Description
  • text/​html
Published
  • Oxford University Press
  • 1993-09-01 00:00:00.0
Language
  • English

Edition details

Title
  • Strong inhibition of fibrinogen binding to platelet receptor {alpha}IIb{beta}3 by RGD sequences installed into a presentation scaffold
Author
  • Lee, Grace
  • Chan, Winnie
  • Hurle, Mark R.
  • DesJarlais, Renee L.
  • Watson, Felicia
  • Sathe, Ganesh M.
  • Wetzel, Ronald
Published
  • Oxford University Press
  • 1993-09-01 00:00:00.0
Physical Description
  • text/​html
Subjects
Notes
  • In order to probe the structural constraints on binding of RGD sequences to the platelet receptor α IIb β 3 we have used recombinant DNA techniques to install the RGD sequence into ‘presentation scaffolds’, small proteins of known 3-D structure chosen to present guest sequences in constrained orientations. Using Escherichia coli expression systems we made sequence variants in which loop residues of the immunoglobulin V L domain REI and of human interleukin-1β were replaced (without changing polypeptide length) by the RGD sequence at positions predicted, based on small molecule studies, to orient the RGD moiety into an active conformation. These variants do not compete for fibrinogen binding to α IIb β 3 up to almost 1 mM concentration. Unfolded or proteolytically fragmented forms of these same proteins do compete, however, showing that the RGD sequences in the mutants must be prohibited from binding by constraints imposed by scaffold structure. To suppress the effects of such structural constraints we constructed two sequence variants in which RGD-containing sequences 42–57 or 44–55 from the snake venom platelet antagonist kistrin were inserted (this increasing the length of the loop) into the third complementarity determining loop of REI. Both of these variants compete strongly for fibrinogen binding with IC 50 s in the nM range. These results, plus data on kistrin-related peptides also presented here, suggest that the molecular scaffold REI is capable of providing to an installed sequence a structural context and conformation beneficial to binding. The results also suggest that in order to bind well to α IIb β 3 , RGD sequences in protein ligands must either project significantly from the surface of the scaffold and&​sol;or retain a degree of conformational flexibility within the scaffold. Molecular scaffolds like REI should prove useful in the elucidation of structure-function relationships and the discovery of new active sequences, and may also serve as the basis for novel therapeutic agents.
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  • English
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