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.
Zhao
B
B
Department of Macromolecular Sciences, SmithKline Beecham Pharmaceuticals, Inc., King of Prussia, Pennsylvania 19406, USA.
Helms
L R
LR
DesJarlais
R L
RL
Abdel-Meguid
S S
SS
Wetzel
R
R
D000595:Amino Acid Sequence; D003461:Crystallography; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid