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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

A paradigm for drug discovery using a conformation from the crystal structure of a presentation scaffold.

We describe a structural validation of the use of presentation scaffolds for control and elucidation of bioactive conformations of peptides. The protein REI-RGD34--produced by inserting the sequence RIPRGDMP into the CDR1 loop region of the immunoglobulin VL domain REI--strongly inhibits fibrinogen binding to the integrins alpha IIb beta 3 and alpha V beta 3. In the X-ray crystal structure of their protein at 2.4 A resolution, the RGD-containing loop exhibits defined electron density that is consistent with models for the bioactive conformations of ligands of these receptors based on previous small-molecule studies. Furthermore, a search of a small-molecule database with conformational information derived from the structure of REI-RGD34 identified constrained peptides and peptidomimetics known to be antagonists of the platelet receptor alpha IIb beta 3.[1]

References

  1. A paradigm for drug discovery using a conformation from the crystal structure of a presentation scaffold. Zhao, B., Helms, L.R., DesJarlais, R.L., Abdel-Meguid, S.S., Wetzel, R. Nat. Struct. Biol. (1995) [Pubmed]
 
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